Renal Impairment
Conditions
Keywords
renal function, sodium-glucose co-transporter, pharmacokinetics, decreased renal function, decreased kidney function, kidney disease, urinary glucose excretion, UGE
Brief summary
The purpose of this trial was to evaluate whether the study drug, LIK066, causes glucose excretion in urine in patients with varying degrees of decreased kidney function and in subjects with normal kidney function. Blood samples were collected to measure the concentrations of LIK066 and to study the pharmacokinetics of LIK066. Pharmacokinetics is meant to study how LIK066 is absorbed, distributed and eliminated, in other words what the body does to the drug. The results of this study may be used to help determine whether LIK066 can be used to treat people with reduced kidney function and the proper dosing regimen.
Interventions
DRUGLIK066
LIK066 50 mg tablets taken orally once daily before breakfast for 7 days.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 78 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent must be obtained before any assessment is performed. * Male and female subjects age 18-78 years, inclusive, with controlled health condition as determined by past medical history, physical examination, electrocardiogram and laboratory test at screening. * patients with Type 2 diabetes, HbA1c \<10% at screening. * Body mass index (BMI) ≤ 50 kg/m\^2 at screening.
Exclusion criteria
* Patients with Type 1 diabetes * Evidence of clinically significant liver function test: ALT, AST, gamma-GT, alkaline phosphatase \>3 X ULN; serum bilirubin \> 1.5 X ULN. * Patients undergoing any method of dialysis * clinically significant GI disorder related to malabsorption or that may affect drug or glucose absorption. * subjects who experienced ketoacidosis, lactic acidosis or hyperosmolar coma within 6 months of screening visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 24-hour Urinary Glucose Excretion (UGE) on Day 7 | Baseline , Day 7 | Urine was collected over 24 h to measure Urinary Glucose Excretion (UGE) at baseline (Day -1), following a single dose (Day 1) and at the end of the 7-day treatment (Day 7) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. |
| Maximum Observed Plasma Concentration (Cmax) for LIK066 | Day 1 and Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose) | Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. Cmax was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done. |
| Time to Reach the Maximum Plasma Concentration (Tmax) for LIK066 | Day 1 and Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose) | Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. Tmax was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done. |
| Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for LIK066 | Day 1 and Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose) | Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. AUCtau was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done. |
| Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) for LIK066 on Day 7 | Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose) | Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. AUClast was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. AUClast is similar to AUCtau on Day 1 since the Tlast for Day 1 = 24hrs (tau = 24hrs); therefore AUClast is not reported for Day1, it is however reported for Day 7 since the Tlast is different from 24 hours. Only descriptive analysis done. |
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) for LIK066 on Day 1 | Day 1 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose) | Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. AUCinf was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. AUCinf is a single dose parameter and therefore is presented on Day 1 only, after the first dose of LIK066. Only descriptive analysis done. |
| Terminal Elimination Half-life (T1/2) for LIK066 on Day 7 | Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose) | Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. T1/2 was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. T1/2 is only reported at Day 7 only, since there was sampling out to \ 5 half-lives after the Day 7 dose of LIK066. Only descriptive analysis done. |
| Apparent Systemic (or Total Body) Clearance From Plasma Following Extravascular Administration (CL/F) for LIK066 on Day 1 | Day 1 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose) | Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. CL/F was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Since Day 7 represented steady state of LIK066 in the study, the appropriately calculated steady-state clearance parameter computed was CLss/F and was presented. Only descriptive analysis done. |
| Apparent Volume of Distribution During the Terminal Elimination Phase Following Extravascular Administration (Vz/F) for LIK066 on Day 1 | Day 1 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose) | Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. Vz/F was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done. |
| Renal Clearance From Plasma (CLr) for LIK066 | Day 1 and Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose) | Urine PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. CLr was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 1 centers in the United States.
Participants by arm
| Arm | Count |
|---|---|
| Mild Patients with mild renal impairment (Group 1) received LIK066 50 mg qd before breakfast for 7 days. | 10 |
| Moderate A Patients with moderate renal impairment grade A (Group 2) received LIK066 50 mg qd before breakfast for 7 days. | 10 |
| Moderate B Patients with moderate renal impairment grade B (Group 3) received LIK066 50 mg qd before breakfast for 7 days. | 11 |
| Severe Patients with severe renal impairment (Group 4) received LIK066 50 mg qd before breakfast for 7 days. | 12 |
| Normal Patients with normal renal function (Group 5) received LIK066 50 mg qd before breakfast for 7 days. | 10 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Subject/Guardian Decision | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Mild | Total | Normal | Severe | Moderate B | Moderate A |
|---|---|---|---|---|---|---|
| 24-hour Urinary glucose excretion (UGE) | 4.7 gram (g) STANDARD_DEVIATION 9.96 | 1.5 gram (g) STANDARD_DEVIATION 5.25 | 0.1 gram (g) STANDARD_DEVIATION 0.07 | 0.3 gram (g) STANDARD_DEVIATION 0.77 | 0.1 gram (g) STANDARD_DEVIATION 0.12 | 2.9 gram (g) STANDARD_DEVIATION 6.27 |
| Age, Continuous | 65.4 Years STANDARD_DEVIATION 9.03 | 64.0 Years STANDARD_DEVIATION 9.66 | 59.3 Years STANDARD_DEVIATION 8.17 | 63.3 Years STANDARD_DEVIATION 12.66 | 65.8 Years STANDARD_DEVIATION 9.1 | 66.3 Years STANDARD_DEVIATION 8.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 14 Participants | 4 Participants | 3 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 38 Participants | 5 Participants | 9 Participants | 8 Participants | 9 Participants |
| Sex: Female, Male Female | 6 Participants | 28 Participants | 6 Participants | 3 Participants | 8 Participants | 5 Participants |
| Sex: Female, Male Male | 4 Participants | 25 Participants | 4 Participants | 9 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 11 | 0 / 12 |
| other Total, other adverse events | 9 / 10 | 10 / 10 | 10 / 10 | 11 / 11 | 11 / 12 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 | 1 / 11 | 1 / 12 |
Outcome results
Primary
Apparent Systemic (or Total Body) Clearance From Plasma Following Extravascular Administration (CL/F) for LIK066 on Day 1
Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. CL/F was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Since Day 7 represented steady state of LIK066 in the study, the appropriately calculated steady-state clearance parameter computed was CLss/F and was presented. Only descriptive analysis done.
Time frame: Day 1 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)
Population: Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only descriptive analysis done.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal | Apparent Systemic (or Total Body) Clearance From Plasma Following Extravascular Administration (CL/F) for LIK066 on Day 1 | 17.4 Liter per hour (L/h) | Standard Deviation 4.2 |
| Mild | Apparent Systemic (or Total Body) Clearance From Plasma Following Extravascular Administration (CL/F) for LIK066 on Day 1 | 14.3 Liter per hour (L/h) | Standard Deviation 2.59 |
| Moderate A | Apparent Systemic (or Total Body) Clearance From Plasma Following Extravascular Administration (CL/F) for LIK066 on Day 1 | 14.9 Liter per hour (L/h) | Standard Deviation 2.55 |
| Moderate B | Apparent Systemic (or Total Body) Clearance From Plasma Following Extravascular Administration (CL/F) for LIK066 on Day 1 | 15.4 Liter per hour (L/h) | Standard Deviation 4.87 |
| Severe | Apparent Systemic (or Total Body) Clearance From Plasma Following Extravascular Administration (CL/F) for LIK066 on Day 1 | 12.4 Liter per hour (L/h) | Standard Deviation 4.53 |
Primary
Apparent Volume of Distribution During the Terminal Elimination Phase Following Extravascular Administration (Vz/F) for LIK066 on Day 1
Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. Vz/F was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done.
Time frame: Day 1 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)
Population: Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only descriptive analysis done.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal | Apparent Volume of Distribution During the Terminal Elimination Phase Following Extravascular Administration (Vz/F) for LIK066 on Day 1 | 160 Liter (L) | Standard Deviation 59.4 |
| Mild | Apparent Volume of Distribution During the Terminal Elimination Phase Following Extravascular Administration (Vz/F) for LIK066 on Day 1 | 140 Liter (L) | Standard Deviation 28.6 |
| Moderate A | Apparent Volume of Distribution During the Terminal Elimination Phase Following Extravascular Administration (Vz/F) for LIK066 on Day 1 | 164 Liter (L) | Standard Deviation 79.9 |
| Moderate B | Apparent Volume of Distribution During the Terminal Elimination Phase Following Extravascular Administration (Vz/F) for LIK066 on Day 1 | 176 Liter (L) | Standard Deviation 67.8 |
| Severe | Apparent Volume of Distribution During the Terminal Elimination Phase Following Extravascular Administration (Vz/F) for LIK066 on Day 1 | 134 Liter (L) | Standard Deviation 50.5 |
Primary
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) for LIK066 on Day 1
Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. AUCinf was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. AUCinf is a single dose parameter and therefore is presented on Day 1 only, after the first dose of LIK066. Only descriptive analysis done.
Time frame: Day 1 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)
Population: Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only descriptive analysis done.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) for LIK066 on Day 1 | 310 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 688 |
| Mild | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) for LIK066 on Day 1 | 3610 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 649 |
| Moderate A | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) for LIK066 on Day 1 | 3440 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 551 |
| Moderate B | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) for LIK066 on Day 1 | 3520 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 1000 |
| Severe | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) for LIK066 on Day 1 | 4450 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 1480 |
Primary
Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for LIK066
Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. AUCtau was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done.
Time frame: Day 1 and Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)
Population: Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only patients with evaluable data at each time point were analyzed for that time point. Only descriptive analysis done.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal | Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for LIK066 | Day 7 | 3440 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 790 |
| Normal | Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for LIK066 | Day 1 | 2830 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 650 |
| Mild | Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for LIK066 | Day 7 | 4170 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 981 |
| Mild | Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for LIK066 | Day 1 | 3330 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 563 |
| Moderate A | Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for LIK066 | Day 1 | 3120 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 567 |
| Moderate A | Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for LIK066 | Day 7 | 4080 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 1040 |
| Moderate B | Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for LIK066 | Day 7 | 4510 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 1240 |
| Moderate B | Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for LIK066 | Day 1 | 3360 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 886 |
| Severe | Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for LIK066 | Day 7 | 6290 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 2280 |
| Severe | Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for LIK066 | Day 1 | 4150 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 1040 |
Primary
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) for LIK066 on Day 7
Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. AUClast was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. AUClast is similar to AUCtau on Day 1 since the Tlast for Day 1 = 24hrs (tau = 24hrs); therefore AUClast is not reported for Day1, it is however reported for Day 7 since the Tlast is different from 24 hours. Only descriptive analysis done.
Time frame: Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)
Population: Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only descriptive analysis done.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal | Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) for LIK066 on Day 7 | 4190 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 1090 |
| Mild | Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) for LIK066 on Day 7 | 5280 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 1540 |
| Moderate A | Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) for LIK066 on Day 7 | 5440 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 1740 |
| Moderate B | Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) for LIK066 on Day 7 | 6410 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 2160 |
| Severe | Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) for LIK066 on Day 7 | 9620 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 3910 |
Primary
Change From Baseline in 24-hour Urinary Glucose Excretion (UGE) on Day 7
Urine was collected over 24 h to measure Urinary Glucose Excretion (UGE) at baseline (Day -1), following a single dose (Day 1) and at the end of the 7-day treatment (Day 7) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function.
Time frame: Baseline , Day 7
Population: Pharmacodynamic Analysis Set (PD), which consisted of all participants with an observed PD value, was considered. Only patients with evaluable data at each time point were analyzed for that time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal | Change From Baseline in 24-hour Urinary Glucose Excretion (UGE) on Day 7 | 40.45 gram (g) | Standard Deviation 21.93 |
| Mild | Change From Baseline in 24-hour Urinary Glucose Excretion (UGE) on Day 7 | 31.87 gram (g) | Standard Deviation 13.79 |
| Moderate A | Change From Baseline in 24-hour Urinary Glucose Excretion (UGE) on Day 7 | 36.27 gram (g) | Standard Deviation 19.51 |
| Moderate B | Change From Baseline in 24-hour Urinary Glucose Excretion (UGE) on Day 7 | 19.88 gram (g) | Standard Deviation 18.66 |
| Severe | Change From Baseline in 24-hour Urinary Glucose Excretion (UGE) on Day 7 | 5.50 gram (g) | Standard Deviation 3.75 |
p-value: 0.15490% CI: [-19.88, 1.45]Regression, Logistic
p-value: 0.34390% CI: [-16.65, 4.55]Regression, Logistic
p-value: 0.00190% CI: [-31.79, 4.55]Regression, Logistic
p-value: 090% CI: [-46, -25.11]Regression, Logistic
Primary
Maximum Observed Plasma Concentration (Cmax) for LIK066
Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. Cmax was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done.
Time frame: Day 1 and Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)
Population: Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only patients with evaluable data at each time point were analyzed for that time point. Only descriptive analysis done.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal | Maximum Observed Plasma Concentration (Cmax) for LIK066 | Day 1 | 565 nanogram per milliliter (ng/mL) | Standard Deviation 176 |
| Normal | Maximum Observed Plasma Concentration (Cmax) for LIK066 | Day 7 | 650 nanogram per milliliter (ng/mL) | Standard Deviation 250 |
| Mild | Maximum Observed Plasma Concentration (Cmax) for LIK066 | Day 7 | 678 nanogram per milliliter (ng/mL) | Standard Deviation 219 |
| Mild | Maximum Observed Plasma Concentration (Cmax) for LIK066 | Day 1 | 590 nanogram per milliliter (ng/mL) | Standard Deviation 176 |
| Moderate A | Maximum Observed Plasma Concentration (Cmax) for LIK066 | Day 7 | 686 nanogram per milliliter (ng/mL) | Standard Deviation 243 |
| Moderate A | Maximum Observed Plasma Concentration (Cmax) for LIK066 | Day 1 | 492 nanogram per milliliter (ng/mL) | Standard Deviation 142 |
| Moderate B | Maximum Observed Plasma Concentration (Cmax) for LIK066 | Day 1 | 569 nanogram per milliliter (ng/mL) | Standard Deviation 147 |
| Moderate B | Maximum Observed Plasma Concentration (Cmax) for LIK066 | Day 7 | 743 nanogram per milliliter (ng/mL) | Standard Deviation 301 |
| Severe | Maximum Observed Plasma Concentration (Cmax) for LIK066 | Day 1 | 650 nanogram per milliliter (ng/mL) | Standard Deviation 199 |
| Severe | Maximum Observed Plasma Concentration (Cmax) for LIK066 | Day 7 | 800 nanogram per milliliter (ng/mL) | Standard Deviation 268 |
Primary
Renal Clearance From Plasma (CLr) for LIK066
Urine PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. CLr was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done.
Time frame: Day 1 and Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)
Population: Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only patients with evaluable data at each time point were analyzed for that time point. Only descriptive analysis done.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal | Renal Clearance From Plasma (CLr) for LIK066 | Day 7 | 0.474 Liter per hour (L/hr) | Standard Deviation 0.275 |
| Normal | Renal Clearance From Plasma (CLr) for LIK066 | Day 1 | 0.389 Liter per hour (L/hr) | Standard Deviation 0.179 |
| Mild | Renal Clearance From Plasma (CLr) for LIK066 | Day 7 | 0.367 Liter per hour (L/hr) | Standard Deviation 0.0815 |
| Mild | Renal Clearance From Plasma (CLr) for LIK066 | Day 1 | 0.348 Liter per hour (L/hr) | Standard Deviation 0.141 |
| Moderate A | Renal Clearance From Plasma (CLr) for LIK066 | Day 1 | 0.259 Liter per hour (L/hr) | Standard Deviation 0.114 |
| Moderate A | Renal Clearance From Plasma (CLr) for LIK066 | Day 7 | 0.294 Liter per hour (L/hr) | Standard Deviation 0.119 |
| Moderate B | Renal Clearance From Plasma (CLr) for LIK066 | Day 1 | 0.173 Liter per hour (L/hr) | Standard Deviation 0.0919 |
| Moderate B | Renal Clearance From Plasma (CLr) for LIK066 | Day 7 | 0.174 Liter per hour (L/hr) | Standard Deviation 0.0636 |
| Severe | Renal Clearance From Plasma (CLr) for LIK066 | Day 1 | 0.0522 Liter per hour (L/hr) | Standard Deviation 0.0237 |
| Severe | Renal Clearance From Plasma (CLr) for LIK066 | Day 7 | 0.0694 Liter per hour (L/hr) | Standard Deviation 0.0461 |
Primary
Terminal Elimination Half-life (T1/2) for LIK066 on Day 7
Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. T1/2 was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. T1/2 is only reported at Day 7 only, since there was sampling out to \ 5 half-lives after the Day 7 dose of LIK066. Only descriptive analysis done.
Time frame: Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)
Population: Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only descriptive analysis done.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal | Terminal Elimination Half-life (T1/2) for LIK066 on Day 7 | 22.9 hour (hr) | Standard Deviation 20.3 |
| Mild | Terminal Elimination Half-life (T1/2) for LIK066 on Day 7 | 21.8 hour (hr) | Standard Deviation 10.8 |
| Moderate A | Terminal Elimination Half-life (T1/2) for LIK066 on Day 7 | 21.1 hour (hr) | Standard Deviation 9.25 |
| Moderate B | Terminal Elimination Half-life (T1/2) for LIK066 on Day 7 | 20.9 hour (hr) | Standard Deviation 8.91 |
| Severe | Terminal Elimination Half-life (T1/2) for LIK066 on Day 7 | 22.8 hour (hr) | Standard Deviation 9.52 |
Primary
Time to Reach the Maximum Plasma Concentration (Tmax) for LIK066
Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. Tmax was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done.
Time frame: Day 1 and Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)
Population: Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only patients with evaluable data at each time point were analyzed for that time point. Only descriptive analysis done.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Normal | Time to Reach the Maximum Plasma Concentration (Tmax) for LIK066 | Day 1 | 1.00 hour (hr) |
| Normal | Time to Reach the Maximum Plasma Concentration (Tmax) for LIK066 | Day 7 | 1.00 hour (hr) |
| Mild | Time to Reach the Maximum Plasma Concentration (Tmax) for LIK066 | Day 7 | 1.03 hour (hr) |
| Mild | Time to Reach the Maximum Plasma Concentration (Tmax) for LIK066 | Day 1 | 1.00 hour (hr) |
| Moderate A | Time to Reach the Maximum Plasma Concentration (Tmax) for LIK066 | Day 7 | 1.00 hour (hr) |
| Moderate A | Time to Reach the Maximum Plasma Concentration (Tmax) for LIK066 | Day 1 | 1.00 hour (hr) |
| Moderate B | Time to Reach the Maximum Plasma Concentration (Tmax) for LIK066 | Day 7 | 1.00 hour (hr) |
| Moderate B | Time to Reach the Maximum Plasma Concentration (Tmax) for LIK066 | Day 1 | 1.00 hour (hr) |
| Severe | Time to Reach the Maximum Plasma Concentration (Tmax) for LIK066 | Day 7 | 1.00 hour (hr) |
| Severe | Time to Reach the Maximum Plasma Concentration (Tmax) for LIK066 | Day 1 | 1.00 hour (hr) |