A Renal Impairment Study for PF-06651600

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.

• PF-06651600 (Drug): PF-06651600 50 mg oral tablets will be administered on Days 1 to 10

Primary outcomes

• 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 outcomes

• 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.

Sex: All, ages: 18 Years to 75 Years, accepts healthy volunteers

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 exclusion criteria for subjects with renal impairment:

* Subjects requiring hemodialysis and peritoneal dialysis
* Screening BP >/=180 mmHg (systolic) or >/=110 mmHg (diastolic)
* Screening 12-lead ECG demonstrating QTcF >470 msec

Participant flow

Outcome results

• Plasma PF-06651600 Maximum Plasma Concentration (Cmax) (Primary), Geometric mean, nanogram per milliliter (ng/mL): Severe Renal Impairment 445.6 +/- 21
• Plasma PF-06651600 Area Under the Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) (Primary), Geometric mean, nanogram*hour per milliliter (ng*hr/mL): Severe Renal Impairment 986.3 +/- 33
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Secondary), Count of participants, Participants: Severe Renal Impairment 3
• Number of Participants With Laboratory Abnormalities (Secondary), Count of participants, Participants: Severe Renal Impairment 1
• Number of Participants With Vital Signs Data Meeting Pre-specified Criteria (Secondary), Count of participants, Participants: Severe Renal Impairment 1
• Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria (Secondary), Count of participants, Participants: Severe Renal Impairment 1

Adverse events

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.

Other adverse events by term

Limitations and caveats: Since the study was terminated, the results of this study was not complete and the interpretation of the study results was limited.

• Results publication: Wojciechowski J, S Purohit V, Huh Y, Banfield C, Nicholas T. Evolution of Ritlecitinib Population Pharmacokinetic Models During Clinical Drug Development. Clin Pharmacokinet. 2023 Dec;62(12):1765-1779. doi: 10.1007/s40262-023-01318-3. Epub 2023 Nov 2. PMID 37917289
• Results publication: Purohit V, Huh Y, Wojciechowski J, Plotka A, Salts S, Antinew J, Dimitrova A, Nicholas T. Leveraging Prior Healthy Participant Pharmacokinetic Data to Evaluate the Impact of Renal and Hepatic Impairment on Ritlecitinib Pharmacokinetics. AAPS J. 2023 Mar 28;25(3):32. doi: 10.1208/s12248-023-00792-8. PMID 36977960

• Study Protocol (PDF, 2019-05-10)
• Statistical Analysis Plan (PDF, 2019-07-01)

• Pfizer CT.gov Call Center, Study director, Pfizer