Renal Impairment
Conditions
Brief summary
This is a Phase 1 non-randomized, open-label, parallel cohort study of PF-06651600 in subjects with severe renal impairment and subjects without renal impairment (Part 1) and in subjects with mild and moderate renal impairment (Part 2).
Detailed description
This is a Phase 1 non-randomized, open-label, parallel cohort, multi-site study to investigate the effect of renal impairment on the pharmacokinetics, safety and tolerability of PF-06651600 after multiple oral doses of 50 mg daily. Subjects will be selected and categorized into normal renal function or renal impairment groups based on their estimated glomerular filtration rate. Part 1: A total of approximately 16 subjects will be enrolled; approximately 8 subjects with severe renal impairment and approximately 8 with normal renal function. After statistical evaluation of results from Part 1, Part 2 may be conducted with approximately 8 subjects each with moderate and mild renal impairment. The total duration of participation from Screening visit to Day 11 will be a maximum of 39 days and from Screening visit to Follow-up/Contact Visit will a maximum of 73 days.
Interventions
DRUGPF-06651600
PF-06651600 50 mg oral tablets will be administered on Days 1 to 10
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Body mass index (BMI) of \>/= 17.5 to \</= 40.0 kg/m2; and a total body weight \> 50 kg (110 lb) Additional inclusion criteria for subjects with renal impairment: * Meet the following eGFR criteria during the screening period based upon MDRD equation: * Severe renal impairment: eGFR \<30 mL/min but not requiring hemodialysis * Moderate renal impairment (Part 2 only): eGFR \>/=30 mL/min and \<60 mL/min * Mild renal impairment (Part 2 only): eGFR between 60 and 89 mL/min * Any form of renal impairment except acute nephritic syndrome (subjects with history of previous nephritic syndrome but in remission can be included) * Stable drug regimen
Exclusion criteria
* Females of child-bearing potential must use an accepted, highly effective contraceptive method * Renal transplant recipients * Urinary incontinence without catheterization * Subjects with clinically significant infections within the past 6 months prior to first dose of study drug, evidence of active or chronic infection requiring oral treatment within 4 weeks prior, history of disseminated herpes simplex or recurrent or disseminated herpes zoster * Subjects with malignancy or with a history of malignancy, with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of skin or cervical carcinoma in situ * HIV, Hepatitis B, or Hepatitis C infection Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma PF-06651600 Maximum Plasma Concentration (Cmax) | On Day 8 and Day 9 predose, and at 0 (predose), 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16 hours after dose on Day 10, and 24 hours after dose on Day 11. | The plasma PF-06651600 Cmax was observed directly from data. |
| Plasma PF-06651600 Area Under the Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) | On Day 8 and Day 9 predose, and at 0 (predose), 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16 hours after dose on Day 10, and 24 hours after dose on Day 11. | Plasma PF-06651600 AUC0-24 was determined using a linear/log trapezoidal method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From Screening (Day -28) through and including up to 35 calendar days after the last administration of investigational product, assessed up to 74 days. | An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE is considered a TEAE is the event started during the effective duration of treatment. All events that started on or after the first dosing day and time/start time, if collected, but before the last dose plus the lag time were flagged as TEAEs. An AE was considered treatment-related if the causality of the AE was assessed to be the investigational product. The causality of AEs was assessed by the investigator using clinical judgment. |
| Number of Participants With Laboratory Abnormalities | At Screening Visit 1 and on Days -1, 5, 11 and early termination day. | Safety laboratory assessments include clinical chemistry, hematology and urinalysis. Serum creatinine was only assessed on Screening visit 2 and on Day 2 and Day 8 for eGFR assessment. The number of participants with laboratory test abnormalities without regard to baseline abnormality was reported. |
| Number of Participants With Vital Signs Data Meeting Pre-specified Criteria | At screening, on Day 1, Day 5, Day 11 and early termination/discontinuation. | Vital signs evaluations included supine blood pressure (BP), pulse rate, and temperature. Criteria for vital signs values included: supine diastolic BP \>= 20 mmHg increase from baseline, supine systolic BP \>= 30 mmHg increase from baseline, supine diastolic BP \>= 20 mmHg decrease from baseline, and supine systolic BP \>= 30 mmHg decrease from baseline. |
| Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria | At screening, on Day -1, Day 11 and early termination/discontinuation. | ECG criteria included PR, QT, and QTc intervals and QRS complex. Participants with absolute data value meeting the following criteria were reported: aggregate PR interval value \>= 300 msec, aggregate QRS duration value \>= 140 msec, absolute QTcF interval value \>450 msec and \<= 480 msec, or \>480 msec and \<=500 msec, or \>500 msec. |
Countries
United States
Participant flow
Recruitment details
The study was terminated, only participants with severe renal impairment were enrolled. Therefore, in this study, data were collected only for participants with severe renal impairment.
Participants by arm
| Arm | Count |
|---|---|
| Severe Renal Impairment Participants with severe renal impairment were included to receive oral PF-06651600 50 mg daily for up to 10 days from Day 1 to Day 10. Stages of renal impairment were based on Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines for Chronic Kidney Disease. | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | Severe Renal Impairment |
|---|---|
| Age, Continuous Mean | 59.5 Years STANDARD_DEVIATION 9.78 |
| Age, Customized 18-44 Years | 1 Participants |
| Age, Customized <18 Years | 0 Participants |
| Age, Customized 45-64 Years | 4 Participants |
| Age, Customized >=65 Years | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants |
| Race/Ethnicity, Customized White | 7 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 3 / 8 | 3 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
Plasma PF-06651600 Area Under the Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24)
Plasma PF-06651600 AUC0-24 was determined using a linear/log trapezoidal method.
Time frame: On Day 8 and Day 9 predose, and at 0 (predose), 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16 hours after dose on Day 10, and 24 hours after dose on Day 11.
Population: The analysis population included all participants assigned to investigational product and treated who had at least 1 of the PK parameters of primary interest measured.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Impairment | Plasma PF-06651600 Area Under the Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) | 986.3 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 33 |
Primary
Plasma PF-06651600 Maximum Plasma Concentration (Cmax)
The plasma PF-06651600 Cmax was observed directly from data.
Time frame: On Day 8 and Day 9 predose, and at 0 (predose), 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16 hours after dose on Day 10, and 24 hours after dose on Day 11.
Population: The analysis population included all participants assigned to investigational product and treated who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Impairment | Plasma PF-06651600 Maximum Plasma Concentration (Cmax) | 445.6 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 21 |
Secondary
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria
ECG criteria included PR, QT, and QTc intervals and QRS complex. Participants with absolute data value meeting the following criteria were reported: aggregate PR interval value \>= 300 msec, aggregate QRS duration value \>= 140 msec, absolute QTcF interval value \>450 msec and \<= 480 msec, or \>480 msec and \<=500 msec, or \>500 msec.
Time frame: At screening, on Day -1, Day 11 and early termination/discontinuation.
Population: The analysis population included all participants assigned to investigational product and who took at least 1 dose of investigational product.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Severe Renal Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria | QTcF interval value >450 msec and <=480 msec | 1 Participants |
| Severe Renal Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria | QRS duration value >= 140 msec | 1 Participants |
Secondary
Number of Participants With Laboratory Abnormalities
Safety laboratory assessments include clinical chemistry, hematology and urinalysis. Serum creatinine was only assessed on Screening visit 2 and on Day 2 and Day 8 for eGFR assessment. The number of participants with laboratory test abnormalities without regard to baseline abnormality was reported.
Time frame: At Screening Visit 1 and on Days -1, 5, 11 and early termination day.
Population: The analysis population included all participants assigned to investigational product and who took at least 1 dose of investigational product.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Severe Renal Impairment | Number of Participants With Laboratory Abnormalities | Erythrocytes <0.8xlower limit of normal (LLN) | 1 Participants |
| Severe Renal Impairment | Number of Participants With Laboratory Abnormalities | Erythrocytes mean corpuscular hemoglobin >1.8*upper limit of normal (ULN) | 1 Participants |
| Severe Renal Impairment | Number of Participants With Laboratory Abnormalities | Lymphocytes/leukocytes <0.8*LLN | 2 Participants |
| Severe Renal Impairment | Number of Participants With Laboratory Abnormalities | Eosinophils/leukocytes >1.2*ULN | 1 Participants |
| Severe Renal Impairment | Number of Participants With Laboratory Abnormalities | Blood urea nitrogen >1.3*ULN | 8 Participants |
| Severe Renal Impairment | Number of Participants With Laboratory Abnormalities | Creatine >1.3*ULN | 8 Participants |
| Severe Renal Impairment | Number of Participants With Laboratory Abnormalities | Urate >1.2*ULN | 6 Participants |
| Severe Renal Impairment | Number of Participants With Laboratory Abnormalities | Bicarbonate <0.9*ULN | 1 Participants |
| Severe Renal Impairment | Number of Participants With Laboratory Abnormalities | Glucose >1.5*ULN | 1 Participants |
| Severe Renal Impairment | Number of Participants With Laboratory Abnormalities | Urine glucose >=1 | 2 Participants |
| Severe Renal Impairment | Number of Participants With Laboratory Abnormalities | Urine protein >=1 | 6 Participants |
| Severe Renal Impairment | Number of Participants With Laboratory Abnormalities | Urine hemoglobin >=1 | 3 Participants |
| Severe Renal Impairment | Number of Participants With Laboratory Abnormalities | Leukocyte esterase >=1 | 2 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE is considered a TEAE is the event started during the effective duration of treatment. All events that started on or after the first dosing day and time/start time, if collected, but before the last dose plus the lag time were flagged as TEAEs. An AE was considered treatment-related if the causality of the AE was assessed to be the investigational product. The causality of AEs was assessed by the investigator using clinical judgment.
Time frame: From Screening (Day -28) through and including up to 35 calendar days after the last administration of investigational product, assessed up to 74 days.
Population: The analysis population included all participants assigned to investigational product and who took at least 1 dose of investigational product.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Severe Renal Impairment | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All-causality TEAEs | 3 Participants |
| Severe Renal Impairment | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related TEAEs | 2 Participants |
Secondary
Number of Participants With Vital Signs Data Meeting Pre-specified Criteria
Vital signs evaluations included supine blood pressure (BP), pulse rate, and temperature. Criteria for vital signs values included: supine diastolic BP \>= 20 mmHg increase from baseline, supine systolic BP \>= 30 mmHg increase from baseline, supine diastolic BP \>= 20 mmHg decrease from baseline, and supine systolic BP \>= 30 mmHg decrease from baseline.
Time frame: At screening, on Day 1, Day 5, Day 11 and early termination/discontinuation.
Population: The analysis population included all participants assigned to investigational product and who took at least 1 dose of investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Severe Renal Impairment | Number of Participants With Vital Signs Data Meeting Pre-specified Criteria | 1 Participants |