Autosomal Dominant Polycystic Kidney Disease
Conditions
Brief summary
This is a Phase 2, open-label, parallel-group, multiple dose study designed to evaluate the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple doses of lixivaptan in Autosomal Dominant Polycystic Kidney Disease subjects with chronic kidney disease (CKD) in stages CKD1, CKD2 or CKD3.
Detailed description
Therapeutic interventions aimed at counterbalancing the effect of vasopressin and/or normalizing intracellular levels of cAMP may be effective in delaying disease progression in autosomal dominant polycystic kidney disease (ADPKD). The primary objectives of this study in subjects with ADPKD are: * To characterize the safety and tolerability of lixivaptan following multiple doses in ADPKD subjects with relatively preserved kidney function (chronic kidney disease CKD1 and CKD2) and moderately impaired renal function (CKD3). The secondary objectives of this study are: * To characterize the PK profile of lixivaptan and its major metabolites following multiple doses of lixivaptan in ADPKD subjects with relatively preserved kidney function (CKD1 and CKD2) and moderately impaired renal function (CKD3). * To characterize the pharmacodynamic effect of lixivaptan on urine output, urine osmolality, total kidney volume, serum vasopressin, and serum creatinine following multiple doses of lixivaptan in ADPKD subjects with relatively preserved kidney function (CKD1 and CKD2) and moderately impaired renal function (CKD3).
Interventions
DRUGLixivaptan
Oral vasopressin V2 receptor antagonist
Sponsors
Palladio Biosciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male or female, between 18 and 65 years of age at the time of screening * Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 with eGFR calculated by the CKD EPI equation * Diagnosed with ADPKD by modified Ravine criteria * Considered by Investigator to be in good health relative to underlying CKD status and clinically stable with respect to underlying CKD
Exclusion criteria
* Known sensitivity or idiosyncratic reaction to lixivaptan, its related compounds such as benzazepines (e.g., tolvaptan, conivaptan, benazepril, fenoldopam, or mirtazapine), or any compound listed as being present in the study formulation * Women who are pregnant or breast feeding * Subjects have taken tolvaptan, oral or intravenous antibiotics, or any investigational drug or used an investigational device within 30 days or 5 half-lives, whichever is longer, prior to first study dose * Subject has a transplanted kidney, or absence of a kidney * Subjects with clinically significant incontinence, overactive bladder, or urinary retention (e.g., benign prostatic hyperplasia) * Subjects with clinically significant liver disease, or clinically significant liver function abnormalities or serology other than that expected for ADPKD with cystic liver disease at baseline * Subjects with any clinically significant concomitant disease or condition other than ADPKD (including treatment for such conditions) that, in the opinion of the Investigator, could either interfere with the study drug or pose an unacceptable risk to the subject
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 7 | Day 7 | The number of study participants who answered not at all and slightly to the following question at Day 7 will be measured: • If the study drug made you go to the bathroom (urinate) more often than usual during the night, did it bother you? |
| Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-138451 in ADPKD Patients | Day 7 (pm) | The pharmacokinetic parameter MRAUC(0-14) for WAY-138451 will be calculated and corrected for molecular weight of WAY-138451 and parent lixivaptan as: (AUC(0-14),m/AUC(0-14),p)(MWp/MWm), where AUC(0-14),m and MWm are AUC(0-14) and molecular weight of WAY-138451, respectively, and AUC(0-14),p and MWp are AUC(0-14) and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRAUC(0-14) calculations: * lixivaptan: 473.93 g/mol * WAY-138451: 488.92 g/mol Results will be summarized by cohort. |
| Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-138758 in ADPKD Patients | Day 7 (pm) | The pharmacokinetic parameter MRAUC(0-14) for WAY-138758 will be calculated and corrected for molecular weight of WAY-138758 and parent lixivaptan as: (AUC(0-14),m/AUC(0-14),p)(MWp/MWm), where AUC(0-14),m and MWm are AUC(0-14) and molecular weight of WAY-138758, respectively, and AUC(0-14),p and MWp are AUC(0-14) and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRAUC(0-14) calculations: * lixivaptan: 473.93 g/mol * WAY-138758: 426.82 g/mol Results will be summarized by cohort. |
| Number of Study Participants With Treatment-emergent Adverse Events | 35 days | The number of study participants who experience treatment-emergent adverse events during the study will be counted and summarized by dose level. |
| Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10 | Day 7 | The number of study participants who answered yes to the following questions at Day 7 will be counted and summarized by dose level: * Could you tolerate taking this dose of study drug for the next 12 months? * Did the study drug make you feel thirsty more often than usual? * Did the study drug make you go to the bathroom (urinate) more often than usual during the night? * Would you be comfortable recommending the study drug to another patient with your kidney condition? |
| Number of Study Participants With Clinically Significant Physical Examination Findings | 35 days | The number of study participants who experience clinically significant physical examination findings during the study will be counted and summarized by cohort. |
| Number of Study Participants With Clinically Significant Vital Signs | 35 days | The number of study participants who experience vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, and body temperature) meeting the predefined markedly abnormal criteria during the study will be counted and summarized by cohort. |
| Number of Study Participants With Clinically Significant Changes in 12-lead Electrocardiograms | Baseline (Day 1) to Day 8 (8 days) | The number of study participants who experience 12-lead electrocardiograms meeting the predefined markedly abnormal criteria during the study will be counted and summarized by cohort. |
| Number of Study Participants With Abnormal Clinical Laboratory Findings (Including Clinical Chemistry, Hematology, and Urinalysis) | 35 days | The number of study participants who experience clinically meaningful laboratory findings, relating to clinical chemistry, hematology, and urinalysis, during the study will be counted and summarized by cohort. |
| Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 3 | Day 7 | The number of study participants who answered not at all and slightly to the following question at Day 7 will be measured: • If the study drug made you feel thirsty more often than usual, were you bothered by it? |
| Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients | Day 1 (am and pm) and Day 7 (am and pm) | The pharmacokinetic parameter Cmax, the highest concentration of lixivaptan measured in plasma after multiple doses of drug, will be calculated from the observed concentration of lixivaptan and summarized by cohort. |
| Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients | Day 1 (am and pm) and Day 7 (am and pm) | The pharmacokinetic parameter Cmax, the highest concentration of WAY-141624 measured in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-141624 and summarized by cohort. |
| Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients | Day 1 (am and pm) and Day 7 (am and pm) | The pharmacokinetic parameter Cmax, the highest concentration of WAY-138451 measured in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-138451 and summarized by cohort. |
| Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients | Day 1 (am and pm) and Day 7 (am and pm) | The pharmacokinetic parameter Cmax, the highest concentration of WAY-138758 measured in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-138758 and summarized by cohort. |
| Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients | Day 1 (am and pm) and Day 7 (am and pm) | The pharmacokinetic parameter tmax, the time taken to reach the highest concentration of lixivaptan in plasma after multiple doses of drug, will be calculated from the observed concentration of lixivaptan and summarized by cohort. |
| Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients | Day 1 (am and pm) and Day 7 (am and pm) | The pharmacokinetic parameter tmax, the time taken to reach the highest concentration of WAY-141624 in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-141624 and summarized by cohort. |
| Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients | Day 1 (am and pm) and Day 7 (am and pm) | The pharmacokinetic parameter tmax, the time taken to reach the highest concentration of WAY-138451 in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-138451 and summarized by cohort. |
| Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients | Day 1 (am and pm) and Day 7 (am and pm) | The pharmacokinetic parameter tmax, the time taken to reach the highest concentration of WAY-138758 in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-138758 and summarized by cohort. |
| Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients | Day 1 (am and pm) and Day 7 (am and pm) | The pharmacokinetic parameter AUC(0-last) for lixivaptan will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values, summarized by cohort. |
| Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients | Day 1 (am and pm) and Day 7 (am and pm) | The pharmacokinetic parameter AUC(0-last) for WAY-141624 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values and summarized by cohort. |
| Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients | Day 1 (am and pm) and Day 7 (am and pm) | The pharmacokinetic parameter AUC(0-last) for WAY-138451 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values and summarized by cohort. |
| Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients | Day 1 (am and pm) and Day 7 (am and pm) | The pharmacokinetic parameter AUC(0-last) for WAY-138758 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values and summarized by cohort. |
| Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) of Lixivaptan in ADPKD Patients | Day 1 (am) | The pharmacokinetic parameter AUC(0-inf) for lixivaptan will be calculated using the linear trapezoidal rule for increasing values, the log trapezoidal rule for decreasing values, and extrapolated to infinity by addition of the last quantifiable observed concentration divided by the elimination rate constant and summarized by cohort. |
| Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) of WAY-141624 in ADPKD Patients | Day 1 (am) | The pharmacokinetic parameter AUC(0-inf) for WAY-141624 will be calculated using the linear trapezoidal rule for increasing values, the log trapezoidal rule for decreasing values, and extrapolated to infinity by addition of the last quantifiable observed concentration divided by the elimination rate constant and summarized by cohort. |
| Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) of WAY-138451 in ADPKD Patients | Day 1 (am) | The pharmacokinetic parameter AUC(0-inf) for WAY-138451 will be calculated using the linear trapezoidal rule for increasing values, the log trapezoidal rule for decreasing values, and extrapolated to infinity by addition of the last quantifiable observed concentration divided by the elimination rate constant and summarized by cohort. |
| Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) of WAY-138758 in ADPKD Patients | Day 1 (am) | The pharmacokinetic parameter AUC(0-inf) for WAY-138758 will be calculated using the linear trapezoidal rule for increasing values, the log trapezoidal rule for decreasing values, and extrapolated to infinity by addition of the last quantifiable observed concentration divided by the elimination rate constant and summarized by cohort. |
| Terminal Elimination Phase Half-life (t1/2) of Lixivaptan in ADPKD Patients | Day 1 (am) and Day 7 (pm) | The pharmacokinetic parameter t1/2 for lixivaptan, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort. |
| Terminal Elimination Phase Half-life (t1/2) of WAY-141624 in ADPKD Patients | Day 1 (am) and Day 7 (pm) | The pharmacokinetic parameter t1/2 for WAY-141624, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort. |
| Terminal Elimination Phase Half-life (t1/2) of WAY-138451 in ADPKD Patients | Day 1 (am) and Day 7 (pm) | The pharmacokinetic parameter t1/2 for WAY-138451, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort. |
| Terminal Elimination Phase Half-life (t1/2) of WAY-138758 in ADPKD Patients | Day 1 (am) and Day 7 (pm) | The pharmacokinetic parameter t1/2 for WAY-138758, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort. |
| Apparent Terminal Elimination Rate Constant (λZ) of Lixivaptan in ADPKD Patients | Day 1 (am) and Day 7 (pm) | The pharmacokinetic parameter λZ for lixivaptan will be determined by linear regression of the terminal points of the log-linear concentration-time curve. The Best Fit method utilized by WinNonlin will be used to identify the terminal linear phase of the concentration-time profile, with visual assessment and adjustment of the selected data points by the PK scientist if warranted. A minimum of 3 data points will be used for determination. Results will be summarized by cohort. |
| Apparent Terminal Elimination Rate Constant (λZ) of WAY-141624 in ADPKD Patients | Day 1 (am) and Day 7 (pm) | The pharmacokinetic parameter λZ for WAY-141624 will be determined by linear regression of the terminal points of the log-linear concentration-time curve. The Best Fit method utilized by WinNonlin will be used to identify the terminal linear phase of the concentration-time profile, with visual assessment and adjustment of the selected data points by the PK scientist if warranted. A minimum of 3 data points will be used for determination. Results will be summarized by cohort. |
| Apparent Terminal Elimination Rate Constant (λZ) of WAY-138451 in ADPKD Patients | Day 1 (am) and Day 7 (pm) | The pharmacokinetic parameter λZ for WAY-138451 will be determined by linear regression of the terminal points of the log-linear concentration-time curve. The Best Fit method utilized by WinNonlin will be used to identify the terminal linear phase of the concentration-time profile, with visual assessment and adjustment of the selected data points by the PK scientist if warranted. A minimum of 3 data points will be used for determination. Results will be summarized by cohort. |
| Apparent Terminal Elimination Rate Constant (λZ) of WAY-138758 in ADPKD Patients | Day 1 (am) and Day 7 (pm) | The pharmacokinetic parameter λZ for WAY-138758 will be determined by linear regression of the terminal points of the log-linear concentration-time curve. The Best Fit method utilized by WinNonlin will be used to identify the terminal linear phase of the concentration-time profile, with visual assessment and adjustment of the selected data points by the PK scientist if warranted. A minimum of 3 data points will be used for determination. Results will be summarized by cohort. |
| Apparent Systemic Clearance After Extravascular Dosing (CL/F) of Lixivaptan in ADPKD Patients | Day 1 (am) and Day 7 (am) | The pharmacokinetic parameter CL/F for lixivaptan, calculated as: Day 1 AM: dose divided by AUC(0-inf), or Day 7 AM: dose divided by AUC(0-last), will be summarized by cohort. |
| Volume of Distribution After Extravascular Dosing (VZ/F) of Lixivaptan in ADPKD Patients | Day 1 (am) and Day 7 (am) | The pharmacokinetic parameter VZ/F for lixivaptan, calculated as CL/F divided by λZ, will be summarized by cohort. |
| Accumulation Ratio for Cmax (RCmax) of Lixivaptan in ADPKD Patients | Day 7 (am) | The pharmacokinetic parameter RCmax for lixivaptan, calculated as \[Cmax on Day 7\]/\[Cmax on Day 1\], will be summarized by cohort. |
| Accumulation Ratio for AUC(0-last) (RAUC[0-last]) of Lixivaptan in ADPKD Patients | Day 7 (am) | The pharmacokinetic parameter RAUC(0-last) for lixivaptan, calculated as \[AUC(0-last) on Day 7\]/\[AUC(0-last) on Day 1\], will be summarized by cohort. |
| Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of Lixivaptan in ADPKD Patients | Day 7 (pm) | The pharmacokinetic parameter AUC(0-14) for lixivaptan will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values. The actual elapsed time for the nominal 14-hour sample will be used for the calculation. Results will be summarized by cohort. |
| Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-141624 in ADPKD Patients | Day 7 (pm) | The pharmacokinetic parameter AUC(0-14) for WAY-141624 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values. The actual elapsed time for the nominal 14-hour sample will be used for the calculation. Results will be summarized by cohort. |
| Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-138451 in ADPKD Patients | Day 7 (pm) | The pharmacokinetic parameter AUC(0-14) for WAY-138451 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values. The actual elapsed time for the nominal 14-hour sample will be used for the calculation. Results will be summarized by cohort. |
| Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-138758 in ADPKD Patients | Day 7 (pm) | The pharmacokinetic parameter AUC(0-14) for WAY-138758 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values. The actual elapsed time for the nominal 14-hour sample will be used for the calculation. Results will be summarized by cohort. |
| Ratio of WAY-141624 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients | Day 7 (pm) | The pharmacokinetic parameter MRCmax for WAY-141624 will be calculated and corrected for molecular weight of WAY-141624 and parent lixivaptan as: (Cmax,m/Cmax,p)(MWp/MWm), where Cmax,m and MWm are Cmax and molecular weight of WAY-141624, respectively, and Cmax,p and MWp are Cmax and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRCmax calculations: * lixivaptan: 473.93 g/mol * WAY-141624: 505.95 g/mol Results will be summarized by cohort. |
| Ratio of WAY-138451 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients | Day 7 (pm) | The pharmacokinetic parameter MRCmax for WAY-138451 will be calculated and corrected for molecular weight of WAY-138451 and parent lixivaptan as: (Cmax,m/Cmax,p)(MWp/MWm), where Cmax,m and MWm are Cmax and molecular weight of WAY-138451, respectively, and Cmax,p and MWp are Cmax and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRCmax calculations: * lixivaptan: 473.93 g/mol * WAY-138451: 488.92 g/mol Results will be summarized by cohort. |
| Ratio of WAY-138758 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients | Day 7 (pm) | The pharmacokinetic parameter MRCmax for WAY-138758 will be calculated and corrected for molecular weight of WAY-138758 and parent lixivaptan as: (Cmax,m/Cmax,p)(MWp/MWm), where Cmax,m and MWm are Cmax and molecular weight of WAY-138758, respectively, and Cmax,p and MWp are Cmax and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRCmax calculations: * lixivaptan: 473.93 g/mol * WAY-138758: 426.82 g/mol Results will be summarized by cohort. |
| Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-141624 in ADPKD Patients | Day 7 (pm) | The pharmacokinetic parameter MRAUC(0-14) for WAY-141624 will be calculated and corrected for molecular weight of WAY-141624 and parent lixivaptan as: (AUC(0-14),m/AUC(0-14),p)(MWp/MWm), where AUC(0-14),m and MWm are AUC(0-14) and molecular weight of WAY-141624, respectively, and AUC(0-14),p and MWp are AUC(0-14) and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRAUC(0-14) calculations: * lixivaptan: 473.93 g/mol * WAY-141624: 505.95 g/mol Results will be summarized by cohort. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Spot Urine Osmolality | At time of dose, and at 1, 2, 4, 6, 9, 10, 11, 12, 14, and 24 hours after the Day 1 and Day 7 doses | Changes from baseline in spot urine measurements for samples taken at 0, 1, 2, 4, 6, 9, 10, 11, 12, 14, and 24 hours after the Day 1 and Day 7 doses will be summarized by cohort. The baseline value for each time point after first administration of study drug is the value observed at the corresponding time point on Day -1 (or Day 1 for the AM predose assessment only). |
| Change From Baseline in 24-hour Urine Output | Baseline (Day -1), Day 1, and Day 7 | Changes from baseline in 24-hour urine output for samples taken on Day 1 and Day 7 will be summarized by cohort. The baseline value was the last value observed prior to first administration of study drug on Day -1. |
| Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR) | Baseline (Day 1) to end of study (35 days) | Changes from baseline of eGFR derived from the serum creatinine concentrations for samples taken at Day 1 (postdose), Day 2, Day 7, Day 8, and Day 35 will summarized by cohort |
| Change From Baseline in Total Kidney Volume | Baseline (Day -1) to end of study (36 days) | Changes from baseline (Day -1) in total kidney volume, measured by abdominal MRI on Day 7 and Day 35, will be summarized by cohort. |
| Change From Baseline in Liver Volume | Baseline (Day -1) to end of study (36 days) | Changes from baseline (Day -1) in liver volume, measured by abdominal MRI on Day 7 and Day 35, will be summarized by cohort. |
| Change From Baseline of Plasma Copeptin | Baseline (Day -1) to end of study (36 days) | Changes from baseline (Day -1) in plasma copeptin, a marker for circulating vasopressin, at Day 2, Day 7, and Day 35 will be summarized by cohort. |
| Change From Baseline in Serum Creatinine | Baseline (Day 1, predose) to end of study (35 days) | Changes from baseline in serum creatinine for samples taken at Day 2, Day 7, Day 8, and Day 35 will be summarized by cohort. |
| Change From Baseline in Blood Urea Nitrogen (BUN) | Baseline (Day 1, predose) to end of study (35 days) | Changes from baseline in BUN for samples taken at Day 2, Day 7, Day 8, and Day 35 will be summarized by cohort. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Volume of Distribution Over 24 Hours After Extravascular Dosing (VZ/F24H) of Lixivaptan in ADPKD Patients | Day 7 (am) | The pharmacokinetic parameter VZ/F24H for lixivaptan, calculated as CL/F24H divided by Day 7 PM λZ, will be summarized by cohort. VZ/F24H was not specified in the statistical analysis plan and was calculated for the combined 24-hour period including AM and PM dosing intervals on Day 7. This parameter replaces VZ/F initially planned for the Day 7 AM dose. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 Oral high dose lixivaptan in participants with CKD1 or CKD2
Lixivaptan: Oral vasopressin V2 receptor antagonist | 9 |
| Low Dose Lixivaptan / CKD1 or CKD2 Oral low dose lixivaptan in participants with CKD1 or CKD2
Lixivaptan: Oral vasopressin V2 receptor antagonist | 7 |
| High Dose Lixivaptan / CKD3 Oral high dose lixivaptan in participants with CKD3
Lixivaptan: Oral vasopressin V2 receptor antagonist | 8 |
| Low Dose Lixivaptan / CKD3 Oral low dose lixivaptan in participants with CKD3
Lixivaptan: Oral vasopressin V2 receptor antagonist | 7 |
| Total | 31 |
Baseline characteristics
| Characteristic | High Dose Lixivaptan / CKD1 or CKD2 | Low Dose Lixivaptan / CKD1 or CKD2 | High Dose Lixivaptan / CKD3 | Low Dose Lixivaptan / CKD3 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 7 Participants | 8 Participants | 7 Participants | 31 Participants |
| Age, Continuous | 40.1 years STANDARD_DEVIATION 16.99 | 34.9 years STANDARD_DEVIATION 10.85 | 54.0 years STANDARD_DEVIATION 9.07 | 51.6 years STANDARD_DEVIATION 10.54 | 45.1 years STANDARD_DEVIATION 14.31 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 4 Participants | 2 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 5 Participants | 4 Participants | 5 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 7 Participants | 8 Participants | 7 Participants | 31 Participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 4 Participants | 4 Participants | 18 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 4 Participants | 3 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 7 | 0 / 8 | 0 / 7 |
| other Total, other adverse events | 2 / 9 | 4 / 7 | 4 / 8 | 4 / 7 |
| serious Total, serious adverse events | 0 / 9 | 0 / 7 | 0 / 8 | 0 / 7 |
Outcome results
Primary
Accumulation Ratio for AUC(0-last) (RAUC[0-last]) of Lixivaptan in ADPKD Patients
The pharmacokinetic parameter RAUC(0-last) for lixivaptan, calculated as \[AUC(0-last) on Day 7\]/\[AUC(0-last) on Day 1\], will be summarized by cohort.
Time frame: Day 7 (am)
Population: Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (am).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Accumulation Ratio for AUC(0-last) (RAUC[0-last]) of Lixivaptan in ADPKD Patients | 2.643 Ratio | Geometric Coefficient of Variation 28.6 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Accumulation Ratio for AUC(0-last) (RAUC[0-last]) of Lixivaptan in ADPKD Patients | 1.795 Ratio | Geometric Coefficient of Variation 25.6 |
| High Dose Lixivaptan / CKD3 | Accumulation Ratio for AUC(0-last) (RAUC[0-last]) of Lixivaptan in ADPKD Patients | 2.365 Ratio | Geometric Coefficient of Variation 28.9 |
| Low Dose Lixivaptan / CKD3 | Accumulation Ratio for AUC(0-last) (RAUC[0-last]) of Lixivaptan in ADPKD Patients | 2.074 Ratio | Geometric Coefficient of Variation 31.5 |
Primary
Accumulation Ratio for Cmax (RCmax) of Lixivaptan in ADPKD Patients
The pharmacokinetic parameter RCmax for lixivaptan, calculated as \[Cmax on Day 7\]/\[Cmax on Day 1\], will be summarized by cohort.
Time frame: Day 7 (am)
Population: Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (am).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Accumulation Ratio for Cmax (RCmax) of Lixivaptan in ADPKD Patients | 2.287 Ratio | Geometric Coefficient of Variation 24.1 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Accumulation Ratio for Cmax (RCmax) of Lixivaptan in ADPKD Patients | 1.687 Ratio | Geometric Coefficient of Variation 68.4 |
| High Dose Lixivaptan / CKD3 | Accumulation Ratio for Cmax (RCmax) of Lixivaptan in ADPKD Patients | 2.087 Ratio | Geometric Coefficient of Variation 36.2 |
| Low Dose Lixivaptan / CKD3 | Accumulation Ratio for Cmax (RCmax) of Lixivaptan in ADPKD Patients | 1.765 Ratio | Geometric Coefficient of Variation 50.1 |
Primary
Apparent Systemic Clearance After Extravascular Dosing (CL/F) of Lixivaptan in ADPKD Patients
The pharmacokinetic parameter CL/F for lixivaptan, calculated as: Day 1 AM: dose divided by AUC(0-inf), or Day 7 AM: dose divided by AUC(0-last), will be summarized by cohort.
Time frame: Day 1 (am) and Day 7 (am)
Population: Upon final PK data analysis, it was evident based upon Day 7 (pm) profiles that lixivaptan did not appear to have concentration-time data in the terminal phase for Day 1 (am) due to the limited time frame of the dosing intervals of 10 hours. Therefore, CL/F, planned for Day 1 (am), was unable to be calculated due to insufficient sampling duration prior to the pm dose. Missing values and substantial deviations meant additional results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Apparent Systemic Clearance After Extravascular Dosing (CL/F) of Lixivaptan in ADPKD Patients | Day 7 (am) | 47.20 L/hour | Geometric Coefficient of Variation 36.8 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Apparent Systemic Clearance After Extravascular Dosing (CL/F) of Lixivaptan in ADPKD Patients | Day 7 (am) | 49.65 L/hour | Geometric Coefficient of Variation 27.7 |
| High Dose Lixivaptan / CKD3 | Apparent Systemic Clearance After Extravascular Dosing (CL/F) of Lixivaptan in ADPKD Patients | Day 7 (am) | 37.07 L/hour | Geometric Coefficient of Variation 35.3 |
| Low Dose Lixivaptan / CKD3 | Apparent Systemic Clearance After Extravascular Dosing (CL/F) of Lixivaptan in ADPKD Patients | Day 7 (am) | 56.22 L/hour | Geometric Coefficient of Variation 29.7 |
| Unknown | Apparent Systemic Clearance After Extravascular Dosing (CL/F) of Lixivaptan in ADPKD Patients | Day 1 (am) | — L/hour | — |
Primary
Apparent Terminal Elimination Rate Constant (λZ) of Lixivaptan in ADPKD Patients
The pharmacokinetic parameter λZ for lixivaptan will be determined by linear regression of the terminal points of the log-linear concentration-time curve. The Best Fit method utilized by WinNonlin will be used to identify the terminal linear phase of the concentration-time profile, with visual assessment and adjustment of the selected data points by the PK scientist if warranted. A minimum of 3 data points will be used for determination. Results will be summarized by cohort.
Time frame: Day 1 (am) and Day 7 (pm)
Population: Upon final PK data analysis, it was evident based upon Day 7 (pm) profiles that lixivaptan did not appear to have concentration-time data in the terminal phase for Day 1 (am) due to the limited time frame of the dosing intervals of 10 hours. Therefore, λZ, planned for Day 1 (am), was unable to be calculated due to insufficient sampling duration prior to the PM dose. Missing values and substantial deviations meant additional results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Apparent Terminal Elimination Rate Constant (λZ) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 0.07149 1/hour | Geometric Coefficient of Variation 24.2 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Apparent Terminal Elimination Rate Constant (λZ) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 0.09016 1/hour | Geometric Coefficient of Variation 51.6 |
| High Dose Lixivaptan / CKD3 | Apparent Terminal Elimination Rate Constant (λZ) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 0.06085 1/hour | Geometric Coefficient of Variation 28.9 |
| Low Dose Lixivaptan / CKD3 | Apparent Terminal Elimination Rate Constant (λZ) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 0.06762 1/hour | Geometric Coefficient of Variation 27.4 |
| Unknown | Apparent Terminal Elimination Rate Constant (λZ) of Lixivaptan in ADPKD Patients | Day 1 (am) | — 1/hour | — |
Primary
Apparent Terminal Elimination Rate Constant (λZ) of WAY-138451 in ADPKD Patients
The pharmacokinetic parameter λZ for WAY-138451 will be determined by linear regression of the terminal points of the log-linear concentration-time curve. The Best Fit method utilized by WinNonlin will be used to identify the terminal linear phase of the concentration-time profile, with visual assessment and adjustment of the selected data points by the PK scientist if warranted. A minimum of 3 data points will be used for determination. Results will be summarized by cohort.
Time frame: Day 1 (am) and Day 7 (pm)
Population: It was evident WAY-138451 did not appear to have concentration-time data in the terminal phase for D1(am) due to the limited time frame of the dosing intervals of 10 hours. λZ, planned for D1(am), was unable to be calculated due to insufficient sampling duration prior to the pm dose. Missing values, deviations, and \<3 quantifiable postdose WAY-138451 concentrations meant results were excluded; also, λZ could not be calculated for the 2 participants in the low dose lixivaptan/CKD3 cohort.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Apparent Terminal Elimination Rate Constant (λZ) of WAY-138451 in ADPKD Patients | Day 7 (pm) | 0.1077 1/hour | Geometric Coefficient of Variation 36.7 |
| High Dose Lixivaptan / CKD3 | Apparent Terminal Elimination Rate Constant (λZ) of WAY-138451 in ADPKD Patients | Day 7 (pm) | 0.07353 1/hour | Geometric Coefficient of Variation 22.6 |
| Low Dose Lixivaptan / CKD3 | Apparent Terminal Elimination Rate Constant (λZ) of WAY-138451 in ADPKD Patients | Day 7 (pm) | NA 1/hour | — |
| Unknown | Apparent Terminal Elimination Rate Constant (λZ) of WAY-138451 in ADPKD Patients | Day 1 (am) | — 1/hour | — |
Primary
Apparent Terminal Elimination Rate Constant (λZ) of WAY-138758 in ADPKD Patients
The pharmacokinetic parameter λZ for WAY-138758 will be determined by linear regression of the terminal points of the log-linear concentration-time curve. The Best Fit method utilized by WinNonlin will be used to identify the terminal linear phase of the concentration-time profile, with visual assessment and adjustment of the selected data points by the PK scientist if warranted. A minimum of 3 data points will be used for determination. Results will be summarized by cohort.
Time frame: Day 1 (am) and Day 7 (pm)
Population: Upon final PK data analysis, it was evident based upon Day 7 (pm) profiles that WAY-138758 did not appear to have concentration-time data in the terminal phase for Day 1 (am) due to the limited time frame of the dosing intervals of 10 hours. Therefore, λZ, planned for Day 1 (am), was unable to be calculated due to insufficient sampling duration prior to the pm dose. Missing values and substantial deviations meant additional results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Apparent Terminal Elimination Rate Constant (λZ) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 0.01421 1/hour | Geometric Coefficient of Variation 25.8 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Apparent Terminal Elimination Rate Constant (λZ) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 0.01367 1/hour | Geometric Coefficient of Variation 8.6 |
| High Dose Lixivaptan / CKD3 | Apparent Terminal Elimination Rate Constant (λZ) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 0.01157 1/hour | Geometric Coefficient of Variation 32.8 |
| Low Dose Lixivaptan / CKD3 | Apparent Terminal Elimination Rate Constant (λZ) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 0.01065 1/hour | Geometric Coefficient of Variation 30.2 |
| Unknown | Apparent Terminal Elimination Rate Constant (λZ) of WAY-138758 in ADPKD Patients | Day 1 (am) | — 1/hour | — |
Primary
Apparent Terminal Elimination Rate Constant (λZ) of WAY-141624 in ADPKD Patients
The pharmacokinetic parameter λZ for WAY-141624 will be determined by linear regression of the terminal points of the log-linear concentration-time curve. The Best Fit method utilized by WinNonlin will be used to identify the terminal linear phase of the concentration-time profile, with visual assessment and adjustment of the selected data points by the PK scientist if warranted. A minimum of 3 data points will be used for determination. Results will be summarized by cohort.
Time frame: Day 1 (am) and Day 7 (pm)
Population: Upon final PK data analysis, it was evident based upon Day 7 (pm) profiles that WAY-141624 did not appear to have concentration-time data in the terminal phase for Day 1 (am) due to the limited time frame of the dosing intervals of 10 hours. Therefore, λZ, planned for Day 1 (am), was unable to be calculated due to insufficient sampling duration prior to the PM dose. Missing values and substantial deviations meant additional results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Apparent Terminal Elimination Rate Constant (λZ) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 0.03384 1/hour | Geometric Coefficient of Variation 33.3 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Apparent Terminal Elimination Rate Constant (λZ) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 0.03093 1/hour | Geometric Coefficient of Variation 56.1 |
| High Dose Lixivaptan / CKD3 | Apparent Terminal Elimination Rate Constant (λZ) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 0.03330 1/hour | Geometric Coefficient of Variation 30.4 |
| Low Dose Lixivaptan / CKD3 | Apparent Terminal Elimination Rate Constant (λZ) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 0.03690 1/hour | Geometric Coefficient of Variation 22.2 |
| Unknown | Apparent Terminal Elimination Rate Constant (λZ) of WAY-141624 in ADPKD Patients | Day 1 (am) | — 1/hour | — |
Primary
Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 3
The number of study participants who answered not at all and slightly to the following question at Day 7 will be measured: • If the study drug made you feel thirsty more often than usual, were you bothered by it?
Time frame: Day 7
Population: Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study. Answers were not received from all participants.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 3 | Answered not at all | 2 Participants |
| High Dose Lixivaptan / CKD1 or CKD2 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 3 | Answered slightly | 4 Participants |
| Low Dose Lixivaptan / CKD1 or CKD2 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 3 | Answered slightly | 2 Participants |
| Low Dose Lixivaptan / CKD1 or CKD2 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 3 | Answered not at all | 2 Participants |
| High Dose Lixivaptan / CKD3 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 3 | Answered slightly | 3 Participants |
| High Dose Lixivaptan / CKD3 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 3 | Answered not at all | 4 Participants |
| Low Dose Lixivaptan / CKD3 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 3 | Answered not at all | 2 Participants |
| Low Dose Lixivaptan / CKD3 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 3 | Answered slightly | 0 Participants |
Primary
Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 7
The number of study participants who answered not at all and slightly to the following question at Day 7 will be measured: • If the study drug made you go to the bathroom (urinate) more often than usual during the night, did it bother you?
Time frame: Day 7
Population: Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study. Answers were not received from all participants.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 7 | Answered not at all | 2 Participants |
| High Dose Lixivaptan / CKD1 or CKD2 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 7 | Answered slightly | 3 Participants |
| Low Dose Lixivaptan / CKD1 or CKD2 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 7 | Answered slightly | 0 Participants |
| Low Dose Lixivaptan / CKD1 or CKD2 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 7 | Answered not at all | 1 Participants |
| High Dose Lixivaptan / CKD3 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 7 | Answered slightly | 1 Participants |
| High Dose Lixivaptan / CKD3 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 7 | Answered not at all | 2 Participants |
| Low Dose Lixivaptan / CKD3 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 7 | Answered not at all | 1 Participants |
| Low Dose Lixivaptan / CKD3 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 7 | Answered slightly | 1 Participants |
Primary
Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10
The number of study participants who answered yes to the following questions at Day 7 will be counted and summarized by dose level: * Could you tolerate taking this dose of study drug for the next 12 months? * Did the study drug make you feel thirsty more often than usual? * Did the study drug make you go to the bathroom (urinate) more often than usual during the night? * Would you be comfortable recommending the study drug to another patient with your kidney condition?
Time frame: Day 7
Population: Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10 | Could you tolerate taking this dose of study drug for the next 12 months? | 7 Participants |
| High Dose Lixivaptan / CKD1 or CKD2 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10 | Did the study drug make you feel thirsty more often than usual? | 7 Participants |
| High Dose Lixivaptan / CKD1 or CKD2 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10 | Did the study drug make you go to the bathroom (urinate) more often than usual during the night? | 6 Participants |
| High Dose Lixivaptan / CKD1 or CKD2 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10 | Would you be comfortable recommending the study drug to another patient with your kidney condition? | 9 Participants |
| Low Dose Lixivaptan / CKD1 or CKD2 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10 | Did the study drug make you feel thirsty more often than usual? | 6 Participants |
| Low Dose Lixivaptan / CKD1 or CKD2 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10 | Did the study drug make you go to the bathroom (urinate) more often than usual during the night? | 3 Participants |
| Low Dose Lixivaptan / CKD1 or CKD2 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10 | Would you be comfortable recommending the study drug to another patient with your kidney condition? | 7 Participants |
| Low Dose Lixivaptan / CKD1 or CKD2 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10 | Could you tolerate taking this dose of study drug for the next 12 months? | 6 Participants |
| High Dose Lixivaptan / CKD3 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10 | Did the study drug make you go to the bathroom (urinate) more often than usual during the night? | 6 Participants |
| High Dose Lixivaptan / CKD3 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10 | Did the study drug make you feel thirsty more often than usual? | 8 Participants |
| High Dose Lixivaptan / CKD3 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10 | Would you be comfortable recommending the study drug to another patient with your kidney condition? | 8 Participants |
| High Dose Lixivaptan / CKD3 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10 | Could you tolerate taking this dose of study drug for the next 12 months? | 7 Participants |
| Low Dose Lixivaptan / CKD3 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10 | Would you be comfortable recommending the study drug to another patient with your kidney condition? | 7 Participants |
| Low Dose Lixivaptan / CKD3 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10 | Did the study drug make you feel thirsty more often than usual? | 4 Participants |
| Low Dose Lixivaptan / CKD3 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10 | Could you tolerate taking this dose of study drug for the next 12 months? | 7 Participants |
| Low Dose Lixivaptan / CKD3 | Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10 | Did the study drug make you go to the bathroom (urinate) more often than usual during the night? | 4 Participants |
Primary
Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) of Lixivaptan in ADPKD Patients
The pharmacokinetic parameter AUC(0-inf) for lixivaptan will be calculated using the linear trapezoidal rule for increasing values, the log trapezoidal rule for decreasing values, and extrapolated to infinity by addition of the last quantifiable observed concentration divided by the elimination rate constant and summarized by cohort.
Time frame: Day 1 (am)
Population: Upon final PK data analysis, it was evident based upon Day 7 PM profiles (sampled out to 96 hours) that lixivaptan did not appear to have concentration-time data in the terminal phase for Day 1 (AM) or Day 7 AM due to the limited time frame of the dosing intervals of 10 hours. Therefore, the terminal slope-related PK parameter of AUC(0-inf), planned in the protocol/SAP for Day 1 AM, was unable to be calculated due to insufficient sampling duration prior to the PM dose.
Primary
Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) of WAY-138451 in ADPKD Patients
The pharmacokinetic parameter AUC(0-inf) for WAY-138451 will be calculated using the linear trapezoidal rule for increasing values, the log trapezoidal rule for decreasing values, and extrapolated to infinity by addition of the last quantifiable observed concentration divided by the elimination rate constant and summarized by cohort.
Time frame: Day 1 (am)
Population: Upon final PK data analysis, it was evident based upon Day 7 PM profiles (sampled out to 96 hours) that WAY-138451 did not appear to have concentration-time data in the terminal phase for Day 1 (AM) or Day 7 AM due to the limited time frame of the dosing intervals of 10 hours. Therefore, the terminal slope-related PK parameter of AUC(0-inf), planned in the protocol/SAP for Day 1 AM, was unable to be calculated due to insufficient sampling duration prior to the PM dose.
Primary
Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) of WAY-138758 in ADPKD Patients
The pharmacokinetic parameter AUC(0-inf) for WAY-138758 will be calculated using the linear trapezoidal rule for increasing values, the log trapezoidal rule for decreasing values, and extrapolated to infinity by addition of the last quantifiable observed concentration divided by the elimination rate constant and summarized by cohort.
Time frame: Day 1 (am)
Population: Upon final PK data analysis, it was evident based upon Day 7 PM profiles (sampled out to 96 hours) that WAY-138758 did not appear to have concentration-time data in the terminal phase for Day 1 (AM) or Day 7 AM due to the limited time frame of the dosing intervals of 10 hours. Therefore, the terminal slope-related PK parameter of AUC(0-inf), planned in the protocol/SAP for Day 1 AM, was unable to be calculated due to insufficient sampling duration prior to the PM dose.
Primary
Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) of WAY-141624 in ADPKD Patients
The pharmacokinetic parameter AUC(0-inf) for WAY-141624 will be calculated using the linear trapezoidal rule for increasing values, the log trapezoidal rule for decreasing values, and extrapolated to infinity by addition of the last quantifiable observed concentration divided by the elimination rate constant and summarized by cohort.
Time frame: Day 1 (am)
Population: Upon final PK data analysis, it was evident based upon Day 7 PM profiles (sampled out to 96 hours) that WAY-141624 did not appear to have concentration-time data in the terminal phase for Day 1 (AM) or Day 7 AM due to the limited time frame of the dosing intervals of 10 hours. Therefore, the terminal slope-related PK parameter of AUC(0-inf), planned in the protocol/SAP for Day 1 AM, was unable to be calculated due to insufficient sampling duration prior to the PM dose.
Primary
Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of Lixivaptan in ADPKD Patients
The pharmacokinetic parameter AUC(0-14) for lixivaptan will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values. The actual elapsed time for the nominal 14-hour sample will be used for the calculation. Results will be summarized by cohort.
Time frame: Day 7 (pm)
Population: Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of Lixivaptan in ADPKD Patients | 6530 ng*h/mL | Geometric Coefficient of Variation 44.3 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of Lixivaptan in ADPKD Patients | 1280 ng*h/mL | Geometric Coefficient of Variation 26.9 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of Lixivaptan in ADPKD Patients | 7800 ng*h/mL | Geometric Coefficient of Variation 55.2 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of Lixivaptan in ADPKD Patients | 1069 ng*h/mL | Geometric Coefficient of Variation 29 |
Primary
Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-138451 in ADPKD Patients
The pharmacokinetic parameter AUC(0-14) for WAY-138451 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values. The actual elapsed time for the nominal 14-hour sample will be used for the calculation. Results will be summarized by cohort.
Time frame: Day 7 (pm)
Population: Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-138451 in ADPKD Patients | 1107 ng*h/mL | Geometric Coefficient of Variation 39.2 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-138451 in ADPKD Patients | 182.8 ng*h/mL | Geometric Coefficient of Variation 33.4 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-138451 in ADPKD Patients | 1270 ng*h/mL | Geometric Coefficient of Variation 50.8 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-138451 in ADPKD Patients | 154.4 ng*h/mL | Geometric Coefficient of Variation 37.7 |
Primary
Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-138758 in ADPKD Patients
The pharmacokinetic parameter AUC(0-14) for WAY-138758 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values. The actual elapsed time for the nominal 14-hour sample will be used for the calculation. Results will be summarized by cohort.
Time frame: Day 7 (pm)
Population: Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-138758 in ADPKD Patients | 10900 ng*h/mL | Geometric Coefficient of Variation 55.6 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-138758 in ADPKD Patients | 4121 ng*h/mL | Geometric Coefficient of Variation 56.9 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-138758 in ADPKD Patients | 10730 ng*h/mL | Geometric Coefficient of Variation 25.3 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-138758 in ADPKD Patients | 4509 ng*h/mL | Geometric Coefficient of Variation 36.2 |
Primary
Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-141624 in ADPKD Patients
The pharmacokinetic parameter AUC(0-14) for WAY-141624 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values. The actual elapsed time for the nominal 14-hour sample will be used for the calculation. Results will be summarized by cohort.
Time frame: Day 7 (pm)
Population: Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-141624 in ADPKD Patients | 5227 ng*h/mL | Geometric Coefficient of Variation 46.6 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-141624 in ADPKD Patients | 1717 ng*h/mL | Geometric Coefficient of Variation 46.6 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-141624 in ADPKD Patients | 5871 ng*h/mL | Geometric Coefficient of Variation 50.7 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-141624 in ADPKD Patients | 1959 ng*h/mL | Geometric Coefficient of Variation 54 |
Primary
Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients
The pharmacokinetic parameter AUC(0-last) for lixivaptan will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values, summarized by cohort.
Time frame: Day 1 (am and pm) and Day 7 (am and pm)
Population: The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. All 31 subjects in the PKAS contributed to the PK data on Day 1 (am); 30 contributed data to Day 1 (pm); 29 contributed data to Day 7 (am), and 27 contributed data to Day 7 (pm). Substantial deviations from planned dosing interval durations and missing values meant results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients | Day 1 (am) | 1688 ng*hour/mL | Geometric Coefficient of Variation 43.5 |
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients | Day 1 (pm) | 3619 ng*hour/mL | Geometric Coefficient of Variation 48.5 |
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients | Day 7 (am) | 4237 ng*hour/mL | Geometric Coefficient of Variation 36.8 |
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 8467 ng*hour/mL | Geometric Coefficient of Variation 47.2 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients | Day 1 (pm) | 782.1 ng*hour/mL | Geometric Coefficient of Variation 15.7 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients | Day 7 (am) | 1007 ng*hour/mL | Geometric Coefficient of Variation 27.7 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 1958 ng*hour/mL | Geometric Coefficient of Variation 80.2 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients | Day 1 (am) | 506.7 ng*hour/mL | Geometric Coefficient of Variation 45 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients | Day 7 (am) | 5395 ng*hour/mL | Geometric Coefficient of Variation 35.3 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients | Day 1 (pm) | 5208 ng*hour/mL | Geometric Coefficient of Variation 46.3 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 12870 ng*hour/mL | Geometric Coefficient of Variation 56.2 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients | Day 1 (am) | 2281 ng*hour/mL | Geometric Coefficient of Variation 37.9 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 1666 ng*hour/mL | Geometric Coefficient of Variation 56 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients | Day 1 (pm) | 782.8 ng*hour/mL | Geometric Coefficient of Variation 24.7 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients | Day 1 (am) | 428.8 ng*hour/mL | Geometric Coefficient of Variation 46.6 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients | Day 7 (am) | 889.4 ng*hour/mL | Geometric Coefficient of Variation 29.7 |
Primary
Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients
The pharmacokinetic parameter AUC(0-last) for WAY-138451 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values and summarized by cohort.
Time frame: Day 1 (am and pm) and Day 7 (am and pm)
Population: The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Missing values, substantial deviations from planned dosing interval durations, and \<3 quantifiable postdose WAY-138451 concentrations meant results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients | Day 1 (am) | 284.7 ng*hour/mL | Geometric Coefficient of Variation 50.3 |
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients | Day 1 (pm) | 532.8 ng*hour/mL | Geometric Coefficient of Variation 65.5 |
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients | Day 7 (am) | 736.8 ng*hour/mL | Geometric Coefficient of Variation 31.2 |
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients | Day 7 (pm) | 1444 ng*hour/mL | Geometric Coefficient of Variation 52.6 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients | Day 1 (pm) | 80.14 ng*hour/mL | Geometric Coefficient of Variation 36.1 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients | Day 7 (am) | 139.7 ng*hour/mL | Geometric Coefficient of Variation 45.1 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients | Day 7 (pm) | 194.6 ng*hour/mL | Geometric Coefficient of Variation 138.3 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients | Day 1 (am) | 77.23 ng*hour/mL | Geometric Coefficient of Variation 24.8 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients | Day 7 (am) | 919.2 ng*hour/mL | Geometric Coefficient of Variation 39.8 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients | Day 1 (pm) | 764.5 ng*hour/mL | Geometric Coefficient of Variation 40.1 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients | Day 7 (pm) | 1867 ng*hour/mL | Geometric Coefficient of Variation 58.8 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients | Day 1 (am) | 373.6 ng*hour/mL | Geometric Coefficient of Variation 44.9 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients | Day 7 (pm) | 137.3 ng*hour/mL | Geometric Coefficient of Variation 46.5 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients | Day 1 (pm) | 74.00 ng*hour/mL | Geometric Coefficient of Variation 26.9 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients | Day 1 (am) | 70.01 ng*hour/mL | Geometric Coefficient of Variation 21.6 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients | Day 7 (am) | 132.9 ng*hour/mL | Geometric Coefficient of Variation 42.4 |
Primary
Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients
The pharmacokinetic parameter AUC(0-last) for WAY-138758 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values and summarized by cohort.
Time frame: Day 1 (am and pm) and Day 7 (am and pm)
Population: The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Missing values and substantial deviations from planned dosing interval durations meant results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients | Day 1 (am) | 1792 ng*hour/mL | Geometric Coefficient of Variation 36.9 |
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients | Day 1 (pm) | 4281 ng*hour/mL | Geometric Coefficient of Variation 35.3 |
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients | Day 7 (am) | 7471 ng*hour/mL | Geometric Coefficient of Variation 54.5 |
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 46910 ng*hour/mL | Geometric Coefficient of Variation 62.8 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients | Day 1 (pm) | 1449 ng*hour/mL | Geometric Coefficient of Variation 50.7 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients | Day 7 (am) | 2919 ng*hour/mL | Geometric Coefficient of Variation 59.2 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 18940 ng*hour/mL | Geometric Coefficient of Variation 51.9 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients | Day 1 (am) | 669.7 ng*hour/mL | Geometric Coefficient of Variation 37.1 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients | Day 7 (am) | 7660 ng*hour/mL | Geometric Coefficient of Variation 24.6 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients | Day 1 (pm) | 3418 ng*hour/mL | Geometric Coefficient of Variation 24.5 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 52560 ng*hour/mL | Geometric Coefficient of Variation 28 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients | Day 1 (am) | 1412 ng*hour/mL | Geometric Coefficient of Variation 51.3 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 23890 ng*hour/mL | Geometric Coefficient of Variation 38.1 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients | Day 1 (pm) | 1212 ng*hour/mL | Geometric Coefficient of Variation 49.2 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients | Day 1 (am) | 485.1 ng*hour/mL | Geometric Coefficient of Variation 65 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients | Day 7 (am) | 3162 ng*hour/mL | Geometric Coefficient of Variation 36.3 |
Primary
Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients
The pharmacokinetic parameter AUC(0-last) for WAY-141624 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values and summarized by cohort.
Time frame: Day 1 (am and pm) and Day 7 (am and pm)
Population: The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Missing values and substantial deviations from planned dosing interval durations meant results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients | Day 1 (am) | 2339 ng*hour/mL | Geometric Coefficient of Variation 44.1 |
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients | Day 1 (pm) | 3963 ng*hour/mL | Geometric Coefficient of Variation 48.7 |
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients | Day 7 (am) | 3440 ng*hour/mL | Geometric Coefficient of Variation 40.4 |
| High Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 11330 ng*hour/mL | Geometric Coefficient of Variation 56.4 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients | Day 1 (pm) | 1214 ng*hour/mL | Geometric Coefficient of Variation 49.3 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients | Day 7 (am) | 1349 ng*hour/mL | Geometric Coefficient of Variation 58.1 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 4174 ng*hour/mL | Geometric Coefficient of Variation 56.3 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients | Day 1 (am) | 669.1 ng*hour/mL | Geometric Coefficient of Variation 48.8 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients | Day 7 (am) | 4196 ng*hour/mL | Geometric Coefficient of Variation 37.7 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients | Day 1 (pm) | 3894 ng*hour/mL | Geometric Coefficient of Variation 29 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 15160 ng*hour/mL | Geometric Coefficient of Variation 54.8 |
| High Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients | Day 1 (am) | 2300 ng*hour/mL | Geometric Coefficient of Variation 43.1 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 4731 ng*hour/mL | Geometric Coefficient of Variation 81.2 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients | Day 1 (pm) | 1266 ng*hour/mL | Geometric Coefficient of Variation 45.7 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients | Day 1 (am) | 716.5 ng*hour/mL | Geometric Coefficient of Variation 54.2 |
| Low Dose Lixivaptan / CKD3 | Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients | Day 7 (am) | 1560 ng*hour/mL | Geometric Coefficient of Variation 56.9 |
Primary
Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients
The pharmacokinetic parameter Cmax, the highest concentration of lixivaptan measured in plasma after multiple doses of drug, will be calculated from the observed concentration of lixivaptan and summarized by cohort.
Time frame: Day 1 (am and pm) and Day 7 (am and pm)
Population: The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Of these, all 31 subjects contributed to the PK data on Day 1 (am); 30 contributed data to Day 1 (pm); and 29 contributed data to Day 7 (am) and (pm).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients | Day 1 (am) | 656.8 ng/mL | Geometric Coefficient of Variation 28.1 |
| High Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients | Day 1 (pm) | 1007 ng/mL | Geometric Coefficient of Variation 36.6 |
| High Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients | Day 7 (am) | 1442 ng/mL | Geometric Coefficient of Variation 34.3 |
| High Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 1582 ng/mL | Geometric Coefficient of Variation 45.8 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients | Day 1 (pm) | 211.5 ng/mL | Geometric Coefficient of Variation 33.5 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients | Day 7 (am) | 339.5 ng/mL | Geometric Coefficient of Variation 19.5 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 301.0 ng/mL | Geometric Coefficient of Variation 13.7 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients | Day 1 (am) | 190.9 ng/mL | Geometric Coefficient of Variation 52 |
| High Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients | Day 7 (am) | 1422 ng/mL | Geometric Coefficient of Variation 48.3 |
| High Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients | Day 1 (pm) | 930.2 ng/mL | Geometric Coefficient of Variation 44.5 |
| High Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 1211 ng/mL | Geometric Coefficient of Variation 90.5 |
| High Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients | Day 1 (am) | 681.3 ng/mL | Geometric Coefficient of Variation 45.9 |
| Low Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 258.8 ng/mL | Geometric Coefficient of Variation 38.4 |
| Low Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients | Day 1 (pm) | 159.5 ng/mL | Geometric Coefficient of Variation 51.9 |
| Low Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients | Day 1 (am) | 156.9 ng/mL | Geometric Coefficient of Variation 66.9 |
| Low Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients | Day 7 (am) | 276.9 ng/mL | Geometric Coefficient of Variation 33.7 |
Primary
Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients
The pharmacokinetic parameter Cmax, the highest concentration of WAY-138451 measured in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-138451 and summarized by cohort.
Time frame: Day 1 (am and pm) and Day 7 (am and pm)
Population: The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Missing values, substantial deviations, and \<3 quantifiable postdose WAY-138451 concentrations meant results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients | Day 1 (am) | 84.33 ng/mL | Geometric Coefficient of Variation 28.3 |
| High Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients | Day 1 (pm) | 117.1 ng/mL | Geometric Coefficient of Variation 38.1 |
| High Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients | Day 7 (am) | 177.4 ng/mL | Geometric Coefficient of Variation 22.8 |
| High Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients | Day 7 (pm) | 189.1 ng/mL | Geometric Coefficient of Variation 35.2 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients | Day 1 (pm) | 25.93 ng/mL | Geometric Coefficient of Variation 25.4 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients | Day 7 (am) | 40.79 ng/mL | Geometric Coefficient of Variation 27.6 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients | Day 7 (pm) | 35.36 ng/mL | Geometric Coefficient of Variation 10.4 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients | Day 1 (am) | 28.83 ng/mL | Geometric Coefficient of Variation 21.4 |
| High Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients | Day 7 (am) | 165.4 ng/mL | Geometric Coefficient of Variation 43.1 |
| High Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients | Day 1 (pm) | 103.3 ng/mL | Geometric Coefficient of Variation 38.3 |
| High Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients | Day 7 (pm) | 155.2 ng/mL | Geometric Coefficient of Variation 74 |
| High Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients | Day 1 (am) | 82.23 ng/mL | Geometric Coefficient of Variation 56.3 |
| Low Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients | Day 7 (pm) | 31.64 ng/mL | Geometric Coefficient of Variation 20.2 |
| Low Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients | Day 1 (pm) | 20.95 ng/mL | Geometric Coefficient of Variation 35.4 |
| Low Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients | Day 1 (am) | 24.74 ng/mL | Geometric Coefficient of Variation 38.6 |
| Low Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients | Day 7 (am) | 33.61 ng/mL | Geometric Coefficient of Variation 36.2 |
Primary
Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients
The pharmacokinetic parameter Cmax, the highest concentration of WAY-138758 measured in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-138758 and summarized by cohort.
Time frame: Day 1 (am and pm) and Day 7 (am and pm)
Population: The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Of these, all 31 subjects contributed to the PK data on Day 1 (am); 30 contributed data to Day 1 (pm); and 29 contributed data to Day 7 (am) and (pm). Substantial deviations from planned dosing interval durations meant additional results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients | Day 1 (am) | 239.3 ng/mL | Geometric Coefficient of Variation 40.3 |
| High Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients | Day 1 (pm) | 354.6 ng/mL | Geometric Coefficient of Variation 32.8 |
| High Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients | Day 7 (am) | 822.3 ng/mL | Geometric Coefficient of Variation 54.4 |
| High Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 861.4 ng/mL | Geometric Coefficient of Variation 56 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients | Day 1 (pm) | 125.5 ng/mL | Geometric Coefficient of Variation 53.8 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients | Day 7 (am) | 320.4 ng/mL | Geometric Coefficient of Variation 60.4 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 326.8 ng/mL | Geometric Coefficient of Variation 56.7 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients | Day 1 (am) | 85.11 ng/mL | Geometric Coefficient of Variation 36.5 |
| High Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients | Day 7 (am) | 833.6 ng/mL | Geometric Coefficient of Variation 25 |
| High Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients | Day 1 (pm) | 275.0 ng/mL | Geometric Coefficient of Variation 26.5 |
| High Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 825.2 ng/mL | Geometric Coefficient of Variation 24 |
| High Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients | Day 1 (am) | 185.2 ng/mL | Geometric Coefficient of Variation 49.7 |
| Low Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 342.2 ng/mL | Geometric Coefficient of Variation 36 |
| Low Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients | Day 1 (pm) | 107.1 ng/mL | Geometric Coefficient of Variation 43.5 |
| Low Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients | Day 1 (am) | 64.26 ng/mL | Geometric Coefficient of Variation 53.9 |
| Low Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients | Day 7 (am) | 343.9 ng/mL | Geometric Coefficient of Variation 35.8 |
Primary
Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients
The pharmacokinetic parameter Cmax, the highest concentration of WAY-141624 measured in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-141624 and summarized by cohort.
Time frame: Day 1 (am and pm) and Day 7 (am and pm)
Population: The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Missing values and substantial deviations from planned dosing interval durations meant results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients | Day 1 (am) | 455.3 ng/mL | Geometric Coefficient of Variation 33.3 |
| High Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients | Day 1 (pm) | 561.7 ng/mL | Geometric Coefficient of Variation 35.4 |
| High Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients | Day 7 (am) | 535.8 ng/mL | Geometric Coefficient of Variation 34.4 |
| High Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 612.6 ng/mL | Geometric Coefficient of Variation 42.3 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients | Day 1 (pm) | 160.8 ng/mL | Geometric Coefficient of Variation 56 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients | Day 7 (am) | 213.8 ng/mL | Geometric Coefficient of Variation 75.4 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 200.1 ng/mL | Geometric Coefficient of Variation 63 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients | Day 1 (am) | 123.7 ng/mL | Geometric Coefficient of Variation 69.7 |
| High Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients | Day 7 (am) | 652.1 ng/mL | Geometric Coefficient of Variation 49 |
| High Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients | Day 1 (pm) | 417.8 ng/mL | Geometric Coefficient of Variation 41.4 |
| High Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 588.5 ng/mL | Geometric Coefficient of Variation 69.2 |
| High Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients | Day 1 (am) | 381.7 ng/mL | Geometric Coefficient of Variation 46.6 |
| Low Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 224.8 ng/mL | Geometric Coefficient of Variation 44.7 |
| Low Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients | Day 1 (pm) | 142.3 ng/mL | Geometric Coefficient of Variation 28.7 |
| Low Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients | Day 1 (am) | 135.3 ng/mL | Geometric Coefficient of Variation 55.5 |
| Low Dose Lixivaptan / CKD3 | Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients | Day 7 (am) | 233.7 ng/mL | Geometric Coefficient of Variation 50.8 |
Primary
Number of Study Participants With Abnormal Clinical Laboratory Findings (Including Clinical Chemistry, Hematology, and Urinalysis)
The number of study participants who experience clinically meaningful laboratory findings, relating to clinical chemistry, hematology, and urinalysis, during the study will be counted and summarized by cohort.
Time frame: 35 days
Population: Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Number of Study Participants With Abnormal Clinical Laboratory Findings (Including Clinical Chemistry, Hematology, and Urinalysis) | Clinical chemistry | 0 Participants |
| High Dose Lixivaptan / CKD1 or CKD2 | Number of Study Participants With Abnormal Clinical Laboratory Findings (Including Clinical Chemistry, Hematology, and Urinalysis) | Urinalysis | 0 Participants |
| High Dose Lixivaptan / CKD1 or CKD2 | Number of Study Participants With Abnormal Clinical Laboratory Findings (Including Clinical Chemistry, Hematology, and Urinalysis) | Hematology | 0 Participants |
| Low Dose Lixivaptan / CKD1 or CKD2 | Number of Study Participants With Abnormal Clinical Laboratory Findings (Including Clinical Chemistry, Hematology, and Urinalysis) | Clinical chemistry | 0 Participants |
| Low Dose Lixivaptan / CKD1 or CKD2 | Number of Study Participants With Abnormal Clinical Laboratory Findings (Including Clinical Chemistry, Hematology, and Urinalysis) | Urinalysis | 0 Participants |
| Low Dose Lixivaptan / CKD1 or CKD2 | Number of Study Participants With Abnormal Clinical Laboratory Findings (Including Clinical Chemistry, Hematology, and Urinalysis) | Hematology | 0 Participants |
| High Dose Lixivaptan / CKD3 | Number of Study Participants With Abnormal Clinical Laboratory Findings (Including Clinical Chemistry, Hematology, and Urinalysis) | Hematology | 0 Participants |
| High Dose Lixivaptan / CKD3 | Number of Study Participants With Abnormal Clinical Laboratory Findings (Including Clinical Chemistry, Hematology, and Urinalysis) | Clinical chemistry | 0 Participants |
| High Dose Lixivaptan / CKD3 | Number of Study Participants With Abnormal Clinical Laboratory Findings (Including Clinical Chemistry, Hematology, and Urinalysis) | Urinalysis | 0 Participants |
| Low Dose Lixivaptan / CKD3 | Number of Study Participants With Abnormal Clinical Laboratory Findings (Including Clinical Chemistry, Hematology, and Urinalysis) | Clinical chemistry | 0 Participants |
| Low Dose Lixivaptan / CKD3 | Number of Study Participants With Abnormal Clinical Laboratory Findings (Including Clinical Chemistry, Hematology, and Urinalysis) | Urinalysis | 0 Participants |
| Low Dose Lixivaptan / CKD3 | Number of Study Participants With Abnormal Clinical Laboratory Findings (Including Clinical Chemistry, Hematology, and Urinalysis) | Hematology | 0 Participants |
Primary
Number of Study Participants With Clinically Significant Changes in 12-lead Electrocardiograms
The number of study participants who experience 12-lead electrocardiograms meeting the predefined markedly abnormal criteria during the study will be counted and summarized by cohort.
Time frame: Baseline (Day 1) to Day 8 (8 days)
Population: Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Number of Study Participants With Clinically Significant Changes in 12-lead Electrocardiograms | 0 Participants |
| Low Dose Lixivaptan / CKD1 or CKD2 | Number of Study Participants With Clinically Significant Changes in 12-lead Electrocardiograms | 0 Participants |
| High Dose Lixivaptan / CKD3 | Number of Study Participants With Clinically Significant Changes in 12-lead Electrocardiograms | 0 Participants |
| Low Dose Lixivaptan / CKD3 | Number of Study Participants With Clinically Significant Changes in 12-lead Electrocardiograms | 0 Participants |
Primary
Number of Study Participants With Clinically Significant Physical Examination Findings
The number of study participants who experience clinically significant physical examination findings during the study will be counted and summarized by cohort.
Time frame: 35 days
Population: Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Number of Study Participants With Clinically Significant Physical Examination Findings | 0 Participants |
| Low Dose Lixivaptan / CKD1 or CKD2 | Number of Study Participants With Clinically Significant Physical Examination Findings | 0 Participants |
| High Dose Lixivaptan / CKD3 | Number of Study Participants With Clinically Significant Physical Examination Findings | 0 Participants |
| Low Dose Lixivaptan / CKD3 | Number of Study Participants With Clinically Significant Physical Examination Findings | 1 Participants |
Primary
Number of Study Participants With Clinically Significant Vital Signs
The number of study participants who experience vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, and body temperature) meeting the predefined markedly abnormal criteria during the study will be counted and summarized by cohort.
Time frame: 35 days
Population: Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Number of Study Participants With Clinically Significant Vital Signs | 0 Participants |
| Low Dose Lixivaptan / CKD1 or CKD2 | Number of Study Participants With Clinically Significant Vital Signs | 0 Participants |
| High Dose Lixivaptan / CKD3 | Number of Study Participants With Clinically Significant Vital Signs | 0 Participants |
| Low Dose Lixivaptan / CKD3 | Number of Study Participants With Clinically Significant Vital Signs | 0 Participants |
Primary
Number of Study Participants With Treatment-emergent Adverse Events
The number of study participants who experience treatment-emergent adverse events during the study will be counted and summarized by dose level.
Time frame: 35 days
Population: Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Number of Study Participants With Treatment-emergent Adverse Events | 2 Participants |
| Low Dose Lixivaptan / CKD1 or CKD2 | Number of Study Participants With Treatment-emergent Adverse Events | 4 Participants |
| High Dose Lixivaptan / CKD3 | Number of Study Participants With Treatment-emergent Adverse Events | 4 Participants |
| Low Dose Lixivaptan / CKD3 | Number of Study Participants With Treatment-emergent Adverse Events | 4 Participants |
Primary
Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-138451 in ADPKD Patients
The pharmacokinetic parameter MRAUC(0-14) for WAY-138451 will be calculated and corrected for molecular weight of WAY-138451 and parent lixivaptan as: (AUC(0-14),m/AUC(0-14),p)(MWp/MWm), where AUC(0-14),m and MWm are AUC(0-14) and molecular weight of WAY-138451, respectively, and AUC(0-14),p and MWp are AUC(0-14) and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRAUC(0-14) calculations: * lixivaptan: 473.93 g/mol * WAY-138451: 488.92 g/mol Results will be summarized by cohort.
Time frame: Day 7 (pm)
Population: Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-138451 in ADPKD Patients | 0.1643 Ratio | Geometric Coefficient of Variation 10.9 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-138451 in ADPKD Patients | 0.1384 Ratio | Geometric Coefficient of Variation 11.3 |
| High Dose Lixivaptan / CKD3 | Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-138451 in ADPKD Patients | 0.1579 Ratio | Geometric Coefficient of Variation 17.5 |
| Low Dose Lixivaptan / CKD3 | Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-138451 in ADPKD Patients | 0.1401 Ratio | Geometric Coefficient of Variation 23.9 |
Primary
Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-138758 in ADPKD Patients
The pharmacokinetic parameter MRAUC(0-14) for WAY-138758 will be calculated and corrected for molecular weight of WAY-138758 and parent lixivaptan as: (AUC(0-14),m/AUC(0-14),p)(MWp/MWm), where AUC(0-14),m and MWm are AUC(0-14) and molecular weight of WAY-138758, respectively, and AUC(0-14),p and MWp are AUC(0-14) and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRAUC(0-14) calculations: * lixivaptan: 473.93 g/mol * WAY-138758: 426.82 g/mol Results will be summarized by cohort.
Time frame: Day 7 (pm)
Population: Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-138758 in ADPKD Patients | 1.854 Ratio | Geometric Coefficient of Variation 64.2 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-138758 in ADPKD Patients | 3.573 Ratio | Geometric Coefficient of Variation 83.1 |
| High Dose Lixivaptan / CKD3 | Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-138758 in ADPKD Patients | 1.528 Ratio | Geometric Coefficient of Variation 53.7 |
| Low Dose Lixivaptan / CKD3 | Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-138758 in ADPKD Patients | 4.685 Ratio | Geometric Coefficient of Variation 39.7 |
Primary
Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-141624 in ADPKD Patients
The pharmacokinetic parameter MRAUC(0-14) for WAY-141624 will be calculated and corrected for molecular weight of WAY-141624 and parent lixivaptan as: (AUC(0-14),m/AUC(0-14),p)(MWp/MWm), where AUC(0-14),m and MWm are AUC(0-14) and molecular weight of WAY-141624, respectively, and AUC(0-14),p and MWp are AUC(0-14) and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRAUC(0-14) calculations: * lixivaptan: 473.93 g/mol * WAY-141624: 505.95 g/mol Results will be summarized by cohort.
Time frame: Day 7 (pm)
Population: Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-141624 in ADPKD Patients | 0.7498 Ratio | Geometric Coefficient of Variation 41 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-141624 in ADPKD Patients | 1.256 Ratio | Geometric Coefficient of Variation 69.7 |
| High Dose Lixivaptan / CKD3 | Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-141624 in ADPKD Patients | 0.7050 Ratio | Geometric Coefficient of Variation 24.1 |
| Low Dose Lixivaptan / CKD3 | Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-141624 in ADPKD Patients | 1.717 Ratio | Geometric Coefficient of Variation 42.7 |
Primary
Ratio of WAY-138451 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients
The pharmacokinetic parameter MRCmax for WAY-138451 will be calculated and corrected for molecular weight of WAY-138451 and parent lixivaptan as: (Cmax,m/Cmax,p)(MWp/MWm), where Cmax,m and MWm are Cmax and molecular weight of WAY-138451, respectively, and Cmax,p and MWp are Cmax and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRCmax calculations: * lixivaptan: 473.93 g/mol * WAY-138451: 488.92 g/mol Results will be summarized by cohort.
Time frame: Day 7 (pm)
Population: Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Ratio of WAY-138451 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients | 0.1159 Ratio | Geometric Coefficient of Variation 17.7 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Ratio of WAY-138451 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients | 0.1139 Ratio | Geometric Coefficient of Variation 14.9 |
| High Dose Lixivaptan / CKD3 | Ratio of WAY-138451 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients | 0.1243 Ratio | Geometric Coefficient of Variation 27.5 |
| Low Dose Lixivaptan / CKD3 | Ratio of WAY-138451 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients | 0.1185 Ratio | Geometric Coefficient of Variation 29.3 |
Primary
Ratio of WAY-138758 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients
The pharmacokinetic parameter MRCmax for WAY-138758 will be calculated and corrected for molecular weight of WAY-138758 and parent lixivaptan as: (Cmax,m/Cmax,p)(MWp/MWm), where Cmax,m and MWm are Cmax and molecular weight of WAY-138758, respectively, and Cmax,p and MWp are Cmax and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRCmax calculations: * lixivaptan: 473.93 g/mol * WAY-138758: 426.82 g/mol Results will be summarized by cohort.
Time frame: Day 7 (pm)
Population: Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Ratio of WAY-138758 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients | 0.6045 Ratio | Geometric Coefficient of Variation 61.7 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Ratio of WAY-138758 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients | 1.205 Ratio | Geometric Coefficient of Variation 56.9 |
| High Dose Lixivaptan / CKD3 | Ratio of WAY-138758 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients | 0.7569 Ratio | Geometric Coefficient of Variation 86 |
| Low Dose Lixivaptan / CKD3 | Ratio of WAY-138758 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients | 1.468 Ratio | Geometric Coefficient of Variation 51.2 |
Primary
Ratio of WAY-141624 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients
The pharmacokinetic parameter MRCmax for WAY-141624 will be calculated and corrected for molecular weight of WAY-141624 and parent lixivaptan as: (Cmax,m/Cmax,p)(MWp/MWm), where Cmax,m and MWm are Cmax and molecular weight of WAY-141624, respectively, and Cmax,p and MWp are Cmax and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRCmax calculations: * lixivaptan: 473.93 g/mol * WAY-141624: 505.95 g/mol Results will be summarized by cohort.
Time frame: Day 7 (pm)
Population: Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Ratio of WAY-141624 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients | 0.3627 Ratio | Geometric Coefficient of Variation 40 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Ratio of WAY-141624 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients | 0.6225 Ratio | Geometric Coefficient of Variation 57.5 |
| High Dose Lixivaptan / CKD3 | Ratio of WAY-141624 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients | 0.4554 Ratio | Geometric Coefficient of Variation 31 |
| Low Dose Lixivaptan / CKD3 | Ratio of WAY-141624 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients | 0.8137 Ratio | Geometric Coefficient of Variation 41.5 |
Primary
Terminal Elimination Phase Half-life (t1/2) of Lixivaptan in ADPKD Patients
The pharmacokinetic parameter t1/2 for lixivaptan, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort.
Time frame: Day 1 (am) and Day 7 (pm)
Population: Upon final PK data analysis, it was evident based upon Day 7 (pm) profiles that lixivaptan did not have concentration-time data in the terminal phase for Day 1 (am) due to the limited time frame of the dosing intervals of 10 hours. Therefore, t1/2, planned for Day 1 (am), was unable to be calculated due to insufficient sampling duration prior to the PM dose. Missing values and substantial deviations meant results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Terminal Elimination Phase Half-life (t1/2) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 9.696 hours | Geometric Coefficient of Variation 24.2 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Terminal Elimination Phase Half-life (t1/2) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 7.688 hours | Geometric Coefficient of Variation 51.6 |
| High Dose Lixivaptan / CKD3 | Terminal Elimination Phase Half-life (t1/2) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 11.39 hours | Geometric Coefficient of Variation 28.9 |
| Low Dose Lixivaptan / CKD3 | Terminal Elimination Phase Half-life (t1/2) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 10.25 hours | Geometric Coefficient of Variation 27.4 |
| Unknown | Terminal Elimination Phase Half-life (t1/2) of Lixivaptan in ADPKD Patients | Day 1 (am) | — hours | — |
Primary
Terminal Elimination Phase Half-life (t1/2) of WAY-138451 in ADPKD Patients
The pharmacokinetic parameter t1/2 for WAY-138451, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort.
Time frame: Day 1 (am) and Day 7 (pm)
Population: It was evident WAY-138451 did not have concentration-time data in the terminal phase for D1(am) due to the limited time frame of the 10-hour dosing intervals. t1/2, planned for Day 1 AM, was unable to be calculated due to insufficient sampling duration prior to the PM dose. Missing values, substantial deviations and \<3 quantifiable postdose WAY-138451 concentrations meant some results were excluded; also, t1/2 could not be calculated for the 2 participants in the low dose lixivaptan/CKD3 cohort.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Terminal Elimination Phase Half-life (t1/2) of WAY-138451 in ADPKD Patients | Day 7 (pm) | 6.439 hours | Geometric Coefficient of Variation 36.7 |
| High Dose Lixivaptan / CKD3 | Terminal Elimination Phase Half-life (t1/2) of WAY-138451 in ADPKD Patients | Day 7 (pm) | 9.426 hours | Geometric Coefficient of Variation 22.6 |
| Low Dose Lixivaptan / CKD3 | Terminal Elimination Phase Half-life (t1/2) of WAY-138451 in ADPKD Patients | Day 7 (pm) | NA hours | — |
| Unknown | Terminal Elimination Phase Half-life (t1/2) of WAY-138451 in ADPKD Patients | Day 1 (am) | — hours | — |
Primary
Terminal Elimination Phase Half-life (t1/2) of WAY-138758 in ADPKD Patients
The pharmacokinetic parameter t1/2 for WAY-138758, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort.
Time frame: Day 1 (am) and Day 7 (pm)
Population: Upon final PK data analysis, it was evident based upon Day 7 (pm) profiles that WAY-138758 did not appear to have concentration-time data in the terminal phase for Day 1 (am) due to the limited time frame of the dosing intervals of 10 hours. Therefore, t1/2, planned for Day 1 (am), was unable to be calculated due to insufficient sampling duration prior to the PM dose. Missing values and substantial deviations meant additional results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Terminal Elimination Phase Half-life (t1/2) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 48.80 hours | Geometric Coefficient of Variation 25.8 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Terminal Elimination Phase Half-life (t1/2) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 50.70 hours | Geometric Coefficient of Variation 8.6 |
| High Dose Lixivaptan / CKD3 | Terminal Elimination Phase Half-life (t1/2) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 59.93 hours | Geometric Coefficient of Variation 32.8 |
| Low Dose Lixivaptan / CKD3 | Terminal Elimination Phase Half-life (t1/2) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 65.11 hours | Geometric Coefficient of Variation 30.2 |
| Unknown | Terminal Elimination Phase Half-life (t1/2) of WAY-138758 in ADPKD Patients | Day 1 (am) | — hours | — |
Primary
Terminal Elimination Phase Half-life (t1/2) of WAY-141624 in ADPKD Patients
The pharmacokinetic parameter t1/2 for WAY-141624, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort.
Time frame: Day 1 (am) and Day 7 (pm)
Population: Upon final PK data analysis, it was evident based upon Day 7 (pm) profiles that WAY-141624 did not have concentration-time data in the terminal phase for Day 1 (am) due to the limited time frame of the dosing intervals of 10 hours. Therefore, t1/2, planned for Day 1 AM, was unable to be calculated due to insufficient sampling duration prior to the PM dose. Missing values and substantial deviations meant results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Terminal Elimination Phase Half-life (t1/2) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 20.48 hours | Geometric Coefficient of Variation 33.3 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Terminal Elimination Phase Half-life (t1/2) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 22.41 hours | Geometric Coefficient of Variation 56.1 |
| High Dose Lixivaptan / CKD3 | Terminal Elimination Phase Half-life (t1/2) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 20.81 hours | Geometric Coefficient of Variation 30.4 |
| Low Dose Lixivaptan / CKD3 | Terminal Elimination Phase Half-life (t1/2) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 18.79 hours | Geometric Coefficient of Variation 22.2 |
| Unknown | Terminal Elimination Phase Half-life (t1/2) of WAY-141624 in ADPKD Patients | Day 1 (am) | — hours | — |
Primary
Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients
The pharmacokinetic parameter tmax, the time taken to reach the highest concentration of lixivaptan in plasma after multiple doses of drug, will be calculated from the observed concentration of lixivaptan and summarized by cohort.
Time frame: Day 1 (am and pm) and Day 7 (am and pm)
Population: The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Of these, all 31 subjects contributed to the PK data on Day 1 (am); 30 contributed data to Day 1 (pm); and 29 contributed data to Day 7 (am) and (pm). Substantial deviations from planned dosing interval durations meant results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients | Day 1 (am) | 1.000 hours |
| High Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients | Day 1 (pm) | 1.000 hours |
| High Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients | Day 7 (am) | 1.000 hours |
| High Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 1.000 hours |
| Low Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients | Day 1 (pm) | 1.000 hours |
| Low Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients | Day 7 (am) | 1.000 hours |
| Low Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 1.000 hours |
| Low Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients | Day 1 (am) | 1.000 hours |
| High Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients | Day 7 (am) | 1.000 hours |
| High Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients | Day 1 (pm) | 1.000 hours |
| High Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 1.000 hours |
| High Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients | Day 1 (am) | 1.000 hours |
| Low Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients | Day 7 (pm) | 0.920 hours |
| Low Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients | Day 1 (pm) | 0.980 hours |
| Low Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients | Day 1 (am) | 1.020 hours |
| Low Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients | Day 7 (am) | 1.000 hours |
Primary
Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients
The pharmacokinetic parameter tmax, the time taken to reach the highest concentration of WAY-138451 in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-138451 and summarized by cohort.
Time frame: Day 1 (am and pm) and Day 7 (am and pm)
Population: The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Missing values, substantial deviations from planned dosing interval durations, and \<3 quantifiable postdose WAY-138451 concentrations meant results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients | Day 1 (am) | 1.000 hours |
| High Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients | Day 1 (pm) | 1.000 hours |
| High Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients | Day 7 (am) | 1.000 hours |
| High Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients | Day 7 (pm) | 1.000 hours |
| Low Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients | Day 1 (pm) | 1.475 hours |
| Low Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients | Day 7 (am) | 1.000 hours |
| Low Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients | Day 7 (pm) | 1.015 hours |
| Low Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients | Day 1 (am) | 1.010 hours |
| High Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients | Day 7 (am) | 2.000 hours |
| High Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients | Day 1 (pm) | 2.000 hours |
| High Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients | Day 7 (pm) | 3.000 hours |
| High Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients | Day 1 (am) | 1.000 hours |
| Low Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients | Day 7 (pm) | 1.000 hours |
| Low Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients | Day 1 (pm) | 0.975 hours |
| Low Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients | Day 1 (am) | 1.020 hours |
| Low Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients | Day 7 (am) | 1.050 hours |
Primary
Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients
The pharmacokinetic parameter tmax, the time taken to reach the highest concentration of WAY-138758 in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-138758 and summarized by cohort.
Time frame: Day 1 (am and pm) and Day 7 (am and pm)
Population: The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. All 31 subjects in the PKAS contributed to the PK data on Day 1 (am); 30 contributed data to Day 1 (pm); and 29 contributed data to Day 7 (am) and (pm). Substantial deviations from planned dosing interval durations and missing values meant results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients | Day 1 (am) | 4.000 hours |
| High Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients | Day 1 (pm) | 4.000 hours |
| High Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients | Day 7 (am) | 4.000 hours |
| High Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 2.000 hours |
| Low Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients | Day 1 (pm) | 4.000 hours |
| Low Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients | Day 7 (am) | 2.030 hours |
| Low Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 3.010 hours |
| Low Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients | Day 1 (am) | 4.030 hours |
| High Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients | Day 7 (am) | 3.000 hours |
| High Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients | Day 1 (pm) | 4.000 hours |
| High Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 4.000 hours |
| High Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients | Day 1 (am) | 9.460 hours |
| Low Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients | Day 7 (pm) | 3.900 hours |
| Low Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients | Day 1 (pm) | 13.400 hours |
| Low Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients | Day 1 (am) | 4.020 hours |
| Low Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients | Day 7 (am) | 5.980 hours |
Primary
Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients
The pharmacokinetic parameter tmax, the time taken to reach the highest concentration of WAY-141624 in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-141624 and summarized by cohort.
Time frame: Day 1 (am and pm) and Day 7 (am and pm)
Population: The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Missing values and substantial deviations from planned dosing interval durations meant results were excluded from subjects at various time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients | Day 1 (am) | 2.000 hours |
| High Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients | Day 1 (pm) | 2.000 hours |
| High Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients | Day 7 (am) | 2.000 hours |
| High Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 2.000 hours |
| Low Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients | Day 1 (pm) | 2.000 hours |
| Low Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients | Day 7 (am) | 2.000 hours |
| Low Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 2.010 hours |
| Low Dose Lixivaptan / CKD1 or CKD2 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients | Day 1 (am) | 2.000 hours |
| High Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients | Day 7 (am) | 2.000 hours |
| High Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients | Day 1 (pm) | 2.000 hours |
| High Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 2.025 hours |
| High Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients | Day 1 (am) | 2.000 hours |
| Low Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients | Day 7 (pm) | 1.920 hours |
| Low Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients | Day 1 (pm) | 1.950 hours |
| Low Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients | Day 1 (am) | 2.000 hours |
| Low Dose Lixivaptan / CKD3 | Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients | Day 7 (am) | 2.000 hours |
Primary
Volume of Distribution After Extravascular Dosing (VZ/F) of Lixivaptan in ADPKD Patients
The pharmacokinetic parameter VZ/F for lixivaptan, calculated as CL/F divided by λZ, will be summarized by cohort.
Time frame: Day 1 (am) and Day 7 (am)
Population: Upon final data analysis, it was evident based upon Day (D) 7(pm) profiles that lixivaptan did not have concentration-time data in the terminal phase for D1(am) due to the limited time frame of the 10-hour dosing intervals. Therefore, VZ/F, planned for D1(am), was unable to be calculated due to insufficient sampling duration prior to the pm dose, and values for the D7(am) time point were not presented. Instead, VZ/F24H was determined and presented as an Other Pre-specified Outcome Measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Unknown | Volume of Distribution After Extravascular Dosing (VZ/F) of Lixivaptan in ADPKD Patients | Day 1 (am) | — L |
| Unknown | Volume of Distribution After Extravascular Dosing (VZ/F) of Lixivaptan in ADPKD Patients | Day 7 (am) | — L |
Secondary
Change From Baseline in 24-hour Urine Output
Changes from baseline in 24-hour urine output for samples taken on Day 1 and Day 7 will be summarized by cohort. The baseline value was the last value observed prior to first administration of study drug on Day -1.
Time frame: Baseline (Day -1), Day 1, and Day 7
Population: The PDAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan. Values were not available for all participants in the PDAS at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in 24-hour Urine Output | Day 1 | 2175.3 mL | Standard Deviation 2629.2 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in 24-hour Urine Output | Day 7 | 1995.6 mL | Standard Deviation 2294 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in 24-hour Urine Output | Day 7 | 1744.6 mL | Standard Deviation 1658.7 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in 24-hour Urine Output | Day 1 | 1794.4 mL | Standard Deviation 1697 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in 24-hour Urine Output | Day 1 | 3041.1 mL | Standard Deviation 889.2 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in 24-hour Urine Output | Day 7 | 1843.6 mL | Standard Deviation 1027.7 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in 24-hour Urine Output | Day 1 | 1329.9 mL | Standard Deviation 916.7 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in 24-hour Urine Output | Day 7 | 458.4 mL | Standard Deviation 2233.7 |
Secondary
Change From Baseline in Blood Urea Nitrogen (BUN)
Changes from baseline in BUN for samples taken at Day 2, Day 7, Day 8, and Day 35 will be summarized by cohort.
Time frame: Baseline (Day 1, predose) to end of study (35 days)
Population: Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Blood Urea Nitrogen (BUN) | Day 2 | 0.0644 mmol/L | Standard Deviation 0.82257 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Blood Urea Nitrogen (BUN) | Day 7 | -0.2000 mmol/L | Standard Deviation 1.17573 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Blood Urea Nitrogen (BUN) | Day 8 | -0.5711 mmol/L | Standard Deviation 1.1474 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Blood Urea Nitrogen (BUN) | Day 35 | 0.0008 mmol/L | Standard Deviation 1.61696 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Blood Urea Nitrogen (BUN) | Day 7 | -0.0614 mmol/L | Standard Deviation 1.29029 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Blood Urea Nitrogen (BUN) | Day 8 | -0.1043 mmol/L | Standard Deviation 1.22296 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Blood Urea Nitrogen (BUN) | Day 35 | -0.1886 mmol/L | Standard Deviation 1.36772 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Blood Urea Nitrogen (BUN) | Day 2 | -0.1743 mmol/L | Standard Deviation 0.43535 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Blood Urea Nitrogen (BUN) | Day 8 | -0.2338 mmol/L | Standard Deviation 1.43097 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Blood Urea Nitrogen (BUN) | Day 7 | -0.7488 mmol/L | Standard Deviation 1.66207 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Blood Urea Nitrogen (BUN) | Day 35 | -0.2338 mmol/L | Standard Deviation 2.08729 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Blood Urea Nitrogen (BUN) | Day 2 | -0.1563 mmol/L | Standard Deviation 1.15821 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Blood Urea Nitrogen (BUN) | Day 35 | 0.2286 mmol/L | Standard Deviation 1.94233 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Blood Urea Nitrogen (BUN) | Day 7 | 0.2014 mmol/L | Standard Deviation 1.59194 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Blood Urea Nitrogen (BUN) | Day 2 | -0.1300 mmol/L | Standard Deviation 1.16973 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Blood Urea Nitrogen (BUN) | Day 8 | -0.1229 mmol/L | Standard Deviation 0.99856 |
Secondary
Change From Baseline in Liver Volume
Changes from baseline (Day -1) in liver volume, measured by abdominal MRI on Day 7 and Day 35, will be summarized by cohort.
Time frame: Baseline (Day -1) to end of study (36 days)
Population: The PDAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan. Values were not available for all participants in the PDAS at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Liver Volume | Day 35 | -6.70 mL | Standard Deviation 86.74 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Liver Volume | Day 7 | 53.04 mL | Standard Deviation 125.51 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Liver Volume | Day 7 | 43.02 mL | Standard Deviation 92.15 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Liver Volume | Day 35 | 28.66 mL | Standard Deviation 99.77 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Liver Volume | Day 7 | 104.01 mL | Standard Deviation 131.21 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Liver Volume | Day 35 | 53.51 mL | Standard Deviation 82.52 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Liver Volume | Day 35 | -11.00 mL | Standard Deviation 109.04 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Liver Volume | Day 7 | -0.03 mL | Standard Deviation 40.98 |
Secondary
Change From Baseline in Serum Creatinine
Changes from baseline in serum creatinine for samples taken at Day 2, Day 7, Day 8, and Day 35 will be summarized by cohort.
Time frame: Baseline (Day 1, predose) to end of study (35 days)
Population: Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Serum Creatinine | Day 2 | 6.7778 umol/L | Standard Deviation 6.13958 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Serum Creatinine | Day 7 | 12.6667 umol/L | Standard Deviation 9.73396 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Serum Creatinine | Day 8 | 11.1111 umol/L | Standard Deviation 11.94199 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Serum Creatinine | Day 35 | 2.4004 umol/L | Standard Deviation 6.87657 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Serum Creatinine | Day 7 | 2.7143 umol/L | Standard Deviation 3.45033 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Serum Creatinine | Day 8 | 2.2857 umol/L | Standard Deviation 3.14718 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Serum Creatinine | Day 35 | 0.8571 umol/L | Standard Deviation 6.59365 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Serum Creatinine | Day 2 | 4.1429 umol/L | Standard Deviation 7.17469 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Serum Creatinine | Day 8 | 17.6250 umol/L | Standard Deviation 12.8167 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Serum Creatinine | Day 7 | 19.2500 umol/L | Standard Deviation 16.88406 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Serum Creatinine | Day 35 | -8.5000 umol/L | Standard Deviation 14.04076 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Serum Creatinine | Day 2 | 4.7500 umol/L | Standard Deviation 13.49868 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Serum Creatinine | Day 35 | 7.5714 umol/L | Standard Deviation 5.12696 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Serum Creatinine | Day 7 | 6.5714 umol/L | Standard Deviation 8.86674 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Serum Creatinine | Day 2 | 4.5714 umol/L | Standard Deviation 5.62308 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Serum Creatinine | Day 8 | 7.5714 umol/L | Standard Deviation 7.48013 |
Secondary
Change From Baseline in Spot Urine Osmolality
Changes from baseline in spot urine measurements for samples taken at 0, 1, 2, 4, 6, 9, 10, 11, 12, 14, and 24 hours after the Day 1 and Day 7 doses will be summarized by cohort. The baseline value for each time point after first administration of study drug is the value observed at the corresponding time point on Day -1 (or Day 1 for the AM predose assessment only).
Time frame: At time of dose, and at 1, 2, 4, 6, 9, 10, 11, 12, 14, and 24 hours after the Day 1 and Day 7 doses
Population: The Pharmacodynamic Analysis Set (PDAS) consisted of all 31 subjects in the Safety analysis set who received lixivaptan. Overall, all 31 subjects contributed PD endpoints to the Day 1/2 assessment; 30 subjects contributed data to the Day 7/8 PD endpoints and scheduled EOS assessments; however, values were not available for all participants at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | Time of Day 7 dose | -173.1 mOsm/kg | Standard Deviation 306.8 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 6 hours post Day 7 dose | -86.4 mOsm/kg | Standard Deviation 122.3 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 12 hours post Day 7 dose | -52.3 mOsm/kg | Standard Deviation 42.6 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 10 hours post Day 1 dose | -7.7 mOsm/kg | Standard Deviation 99.4 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 4 hours post Day 7 dose | -78.3 mOsm/kg | Standard Deviation 185 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 4 hours post Day 1 dose | -64.9 mOsm/kg | Standard Deviation 124.3 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 9 hours post Day 7 dose | -100.4 mOsm/kg | Standard Deviation 152.3 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 11 hours post Day 1 dose | -35.6 mOsm/kg | Standard Deviation 60.9 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 14 hours post Day 7 dose | -141.4 mOsm/kg | Standard Deviation 271.8 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 24 hours post Day 7 dose | -219.8 mOsm/kg | Standard Deviation 202.5 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 11 hours post Day 7 dose | -37.0 mOsm/kg | Standard Deviation 49.1 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 12 hours post Day 1 dose | -49.6 mOsm/kg | Standard Deviation 48.1 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 6 hours post Day 1 dose | -68.8 mOsm/kg | Standard Deviation 80.5 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 2 hours post Day 1 dose | -10.1 mOsm/kg | Standard Deviation 25.1 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 2 hours post Day 7 dose | -2.9 mOsm/kg | Standard Deviation 20.6 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 14 hours post Day 1 dose | -139.0 mOsm/kg | Standard Deviation 248.4 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 1 hour post Day 1 dose | -101.9 mOsm/kg | Standard Deviation 150.2 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 1 hour post Day 7 dose | -101.1 mOsm/kg | Standard Deviation 169.1 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 10 hours post Day 7 dose | -54.9 mOsm/kg | Standard Deviation 238.4 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 24 hours post Day 1 dose | -115.2 mOsm/kg | Standard Deviation 118.8 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 9 hours post Day 1 dose | -62.8 mOsm/kg | Standard Deviation 85.3 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | Time of Day 1 dose | -27.7 mOsm/kg | Standard Deviation 253.8 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | Time of Day 1 dose | -28.4 mOsm/kg | Standard Deviation 183.5 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | Time of Day 7 dose | -23.7 mOsm/kg | Standard Deviation 296.2 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 14 hours post Day 7 dose | -25.0 mOsm/kg | Standard Deviation 21.5 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 1 hour post Day 7 dose | -22.6 mOsm/kg | Standard Deviation 63.4 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 6 hours post Day 7 dose | 16.6 mOsm/kg | Standard Deviation 167.4 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 2 hours post Day 7 dose | -13.0 mOsm/kg | Standard Deviation 69.7 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 4 hours post Day 1 dose | -43.7 mOsm/kg | Standard Deviation 36.1 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 4 hours post Day 7 dose | -5.3 mOsm/kg | Standard Deviation 98.8 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 24 hours post Day 7 dose | 104.3 mOsm/kg | Standard Deviation 257 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 6 hours post Day 1 dose | -6.0 mOsm/kg | Standard Deviation 73.5 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 12 hours post Day 7 dose | -67.0 mOsm/kg | Standard Deviation 55.5 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 9 hours post Day 1 dose | -46.6 mOsm/kg | Standard Deviation 240.7 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 1 hour post Day 1 dose | 6.1 mOsm/kg | Standard Deviation 60.1 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 10 hours post Day 1 dose | -8.4 mOsm/kg | Standard Deviation 114.7 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 9 hours post Day 7 dose | -80.6 mOsm/kg | Standard Deviation 211.5 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 11 hours post Day 7 dose | -51.3 mOsm/kg | Standard Deviation 106.2 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 11 hours post Day 1 dose | -41.1 mOsm/kg | Standard Deviation 84.5 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 12 hours post Day 1 dose | -61.9 mOsm/kg | Standard Deviation 88.1 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 10 hours post Day 7 dose | -8.6 mOsm/kg | Standard Deviation 189.4 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 14 hours post Day 1 dose | -60.9 mOsm/kg | Standard Deviation 124.3 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 2 hours post Day 1 dose | -41.6 mOsm/kg | Standard Deviation 64.3 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Spot Urine Osmolality | 24 hours post Day 1 dose | 20.4 mOsm/kg | Standard Deviation 252.6 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 2 hours post Day 1 dose | -86.0 mOsm/kg | Standard Deviation 147.1 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | Time of Day 1 dose | -52.3 mOsm/kg | Standard Deviation 56.1 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 1 hour post Day 1 dose | -44.2 mOsm/kg | Standard Deviation 68.7 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 24 hours post Day 7 dose | -199.4 mOsm/kg | Standard Deviation 135.5 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 4 hours post Day 1 dose | -26.6 mOsm/kg | Standard Deviation 16.6 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 6 hours post Day 1 dose | -72.9 mOsm/kg | Standard Deviation 89.6 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 9 hours post Day 1 dose | -84.6 mOsm/kg | Standard Deviation 78.6 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 10 hours post Day 1 dose | -45.0 mOsm/kg | Standard Deviation 73.2 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 11 hours post Day 1 dose | -70.3 mOsm/kg | Standard Deviation 58.3 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 12 hours post Day 1 dose | -112.1 mOsm/kg | Standard Deviation 144.6 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 14 hours post Day 1 dose | -99.7 mOsm/kg | Standard Deviation 82.1 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 24 hours post Day 1 dose | -110.4 mOsm/kg | Standard Deviation 111.7 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | Time of Day 7 dose | -150.7 mOsm/kg | Standard Deviation 91.2 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 1 hour post Day 7 dose | -114.7 mOsm/kg | Standard Deviation 173.3 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 2 hours post Day 7 dose | -88.1 mOsm/kg | Standard Deviation 158.9 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 4 hours post Day 7 dose | -13.4 mOsm/kg | Standard Deviation 33.7 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 6 hours post Day 7 dose | -57.6 mOsm/kg | Standard Deviation 96.7 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 9 hours post Day 7 dose | -44.3 mOsm/kg | Standard Deviation 71.7 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 10 hours post Day 7 dose | -7.0 mOsm/kg | Standard Deviation 72.1 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 11 hours post Day 7 dose | -63.0 mOsm/kg | Standard Deviation 48.7 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 12 hours post Day 7 dose | -128.7 mOsm/kg | Standard Deviation 141 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 14 hours post Day 7 dose | -83.0 mOsm/kg | Standard Deviation 100.9 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 24 hours post Day 1 dose | -37.9 mOsm/kg | Standard Deviation 104.5 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 24 hours post Day 7 dose | 35.4 mOsm/kg | Standard Deviation 66.4 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 9 hours post Day 7 dose | -36.3 mOsm/kg | Standard Deviation 137.6 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 14 hours post Day 1 dose | -67.3 mOsm/kg | Standard Deviation 63.7 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 12 hours post Day 1 dose | -76.6 mOsm/kg | Standard Deviation 90.3 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 14 hours post Day 7 dose | -47.3 mOsm/kg | Standard Deviation 51.2 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 10 hours post Day 7 dose | 30.4 mOsm/kg | Standard Deviation 176.4 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 11 hours post Day 1 dose | -55.0 mOsm/kg | Standard Deviation 113.8 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 10 hours post Day 1 dose | -5.7 mOsm/kg | Standard Deviation 127.9 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 1 hour post Day 1 dose | -114.7 mOsm/kg | Standard Deviation 95 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 11 hours post Day 7 dose | -48.7 mOsm/kg | Standard Deviation 118.8 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 9 hours post Day 1 dose | -54.1 mOsm/kg | Standard Deviation 93.2 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 6 hours post Day 1 dose | -40.7 mOsm/kg | Standard Deviation 87 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | Time of Day 1 dose | -167.3 mOsm/kg | Standard Deviation 63.4 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 12 hours post Day 7 dose | -80.3 mOsm/kg | Standard Deviation 97.3 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 4 hours post Day 1 dose | -48.7 mOsm/kg | Standard Deviation 77.5 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 4 hours post Day 7 dose | -31.1 mOsm/kg | Standard Deviation 77.4 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 2 hours post Day 7 dose | -63.1 mOsm/kg | Standard Deviation 86.7 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 1 hour post Day 7 dose | -100.7 mOsm/kg | Standard Deviation 135 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 2 hours post Day 1 dose | -68.1 mOsm/kg | Standard Deviation 69.8 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | 6 hours post Day 7 dose | -6.9 mOsm/kg | Standard Deviation 122.6 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Spot Urine Osmolality | Time of Day 7 dose | -97.4 mOsm/kg | Standard Deviation 176.7 |
Secondary
Change From Baseline in Total Kidney Volume
Changes from baseline (Day -1) in total kidney volume, measured by abdominal MRI on Day 7 and Day 35, will be summarized by cohort.
Time frame: Baseline (Day -1) to end of study (36 days)
Population: The PDAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan. Overall, all 31 subjects contributed PD endpoints to the Day 1/2 assessment; 30 subjects contributed data to the Day 7/8 PD endpoints and scheduled EOS assessments; however, values were not available for all participants at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Total Kidney Volume | Day 7 | -8.75 mL | Standard Deviation 42.47 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Total Kidney Volume | Day 35 | -26.63 mL | Standard Deviation 77.84 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Total Kidney Volume | Day 35 | -3.78 mL | Standard Deviation 26.06 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline in Total Kidney Volume | Day 7 | 4.97 mL | Standard Deviation 30.84 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Total Kidney Volume | Day 7 | -66.19 mL | Standard Deviation 141.47 |
| High Dose Lixivaptan / CKD3 | Change From Baseline in Total Kidney Volume | Day 35 | -4.29 mL | Standard Deviation 81.27 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Total Kidney Volume | Day 7 | 23.58 mL | Standard Deviation 33.69 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline in Total Kidney Volume | Day 35 | 28.88 mL | Standard Deviation 68.16 |
Secondary
Change From Baseline of Plasma Copeptin
Changes from baseline (Day -1) in plasma copeptin, a marker for circulating vasopressin, at Day 2, Day 7, and Day 35 will be summarized by cohort.
Time frame: Baseline (Day -1) to end of study (36 days)
Population: The PDAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan. Of these, all 31 subjects contributed PD endpoints to the Day 1/2 assessment; 30 subjects contributed data to the Day 7/8 PD endpoints and scheduled EOS assessments.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline of Plasma Copeptin | Day 2 | 5.072 pmol/L | Standard Deviation 4.798 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline of Plasma Copeptin | Day 35 | 2.111 pmol/L | Standard Deviation 2.829 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline of Plasma Copeptin | Day 7 | 9.745 pmol/L | Standard Deviation 4.91 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline of Plasma Copeptin | Day 2 | 1.986 pmol/L | Standard Deviation 3.286 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline of Plasma Copeptin | Day 35 | 2.786 pmol/L | Standard Deviation 5.498 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline of Plasma Copeptin | Day 7 | 3.016 pmol/L | Standard Deviation 3.392 |
| High Dose Lixivaptan / CKD3 | Change From Baseline of Plasma Copeptin | Day 7 | 17.906 pmol/L | Standard Deviation 10.321 |
| High Dose Lixivaptan / CKD3 | Change From Baseline of Plasma Copeptin | Day 2 | 12.655 pmol/L | Standard Deviation 15.527 |
| High Dose Lixivaptan / CKD3 | Change From Baseline of Plasma Copeptin | Day 35 | -0.943 pmol/L | Standard Deviation 8.435 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline of Plasma Copeptin | Day 2 | -1.986 pmol/L | Standard Deviation 10.893 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline of Plasma Copeptin | Day 35 | -3.337 pmol/L | Standard Deviation 13.993 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline of Plasma Copeptin | Day 7 | 34.519 pmol/L | Standard Deviation 89.262 |
Secondary
Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR)
Changes from baseline of eGFR derived from the serum creatinine concentrations for samples taken at Day 1 (postdose), Day 2, Day 7, Day 8, and Day 35 will summarized by cohort
Time frame: Baseline (Day 1) to end of study (35 days)
Population: The PDAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan. Of these, all 31 subjects contributed PD endpoints to the Day 1/2 assessment; 30 subjects contributed data to the Day 7/8 PD endpoints and scheduled EOS assessments.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR) | Day 2 | -7.4 mL/min/1.73 m² | Standard Deviation 7.2 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR) | Day 7 | -11.9 mL/min/1.73 m² | Standard Deviation 10 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR) | Day 8 | -9.1 mL/min/1.73 m² | Standard Deviation 12.5 |
| High Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR) | Day 35 | -0.9 mL/min/1.73 m² | Standard Deviation 8.4 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR) | Day 7 | -3.0 mL/min/1.73 m² | Standard Deviation 3.7 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR) | Day 35 | 0.0 mL/min/1.73 m² | Standard Deviation 8.3 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR) | Day 2 | -3.9 mL/min/1.73 m² | Standard Deviation 8.8 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR) | Day 8 | -2.9 mL/min/1.73 m² | Standard Deviation 3.3 |
| High Dose Lixivaptan / CKD3 | Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR) | Day 2 | -2.1 mL/min/1.73 m² | Standard Deviation 4.3 |
| High Dose Lixivaptan / CKD3 | Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR) | Day 35 | 2.1 mL/min/1.73 m² | Standard Deviation 4.3 |
| High Dose Lixivaptan / CKD3 | Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR) | Day 8 | -5.5 mL/min/1.73 m² | Standard Deviation 4.8 |
| High Dose Lixivaptan / CKD3 | Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR) | Day 7 | -5.3 mL/min/1.73 m² | Standard Deviation 3.7 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR) | Day 35 | -3.7 mL/min/1.73 m² | Standard Deviation 3.2 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR) | Day 2 | -1.9 mL/min/1.73 m² | Standard Deviation 3.1 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR) | Day 7 | -3.4 mL/min/1.73 m² | Standard Deviation 4.1 |
| Low Dose Lixivaptan / CKD3 | Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR) | Day 8 | -3.4 mL/min/1.73 m² | Standard Deviation 3.5 |
Other Pre-specified
Volume of Distribution Over 24 Hours After Extravascular Dosing (VZ/F24H) of Lixivaptan in ADPKD Patients
The pharmacokinetic parameter VZ/F24H for lixivaptan, calculated as CL/F24H divided by Day 7 PM λZ, will be summarized by cohort. VZ/F24H was not specified in the statistical analysis plan and was calculated for the combined 24-hour period including AM and PM dosing intervals on Day 7. This parameter replaces VZ/F initially planned for the Day 7 AM dose.
Time frame: Day 7 (am)
Population: Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (am). Data were excluded for 1 subject in the low dose/CKD1 or 2 cohort from Day 1 (pm) onwards due to substantial deviations from planned dosing interval durations. Missing values and substantial deviations meant additional results were excluded from subjects at various time points.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose Lixivaptan / CKD1 or CKD2 | Volume of Distribution Over 24 Hours After Extravascular Dosing (VZ/F24H) of Lixivaptan in ADPKD Patients | 547.4 L | Geometric Coefficient of Variation 57.4 |
| Low Dose Lixivaptan / CKD1 or CKD2 | Volume of Distribution Over 24 Hours After Extravascular Dosing (VZ/F24H) of Lixivaptan in ADPKD Patients | 546.0 L | Geometric Coefficient of Variation 48.2 |
| High Dose Lixivaptan / CKD3 | Volume of Distribution Over 24 Hours After Extravascular Dosing (VZ/F24H) of Lixivaptan in ADPKD Patients | 515.1 L | Geometric Coefficient of Variation 50.7 |
| Low Dose Lixivaptan / CKD3 | Volume of Distribution Over 24 Hours After Extravascular Dosing (VZ/F24H) of Lixivaptan in ADPKD Patients | 731.8 L | Geometric Coefficient of Variation 38.4 |