Study of PF-05221304 in Subjects With Varying Degrees of Hepatic Impairment

Study Overview
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Brief Summary
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Hepatic impairment PK study

Detailed Description
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This is a non randomized, open label, single dose, parallel cohort, multisite study to investigate the effect of varying degrees of hepatic impairment on the plasma pharmacokinetics (total and unbound) of PF-05221304 after a single oral dose administered in the fed state.

Official Title
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A PHASE 1, NON-RANDOMIZED, OPEN-LABEL, SINGLE-DOSE, PARALLEL COHORT STUDY TO COMPARE THE PHARMACOKINETICS OF PF-05221304 IN ADULT SUBJECTS WITH VARYING DEGREES OF HEPATIC IMPAIRMENT RELATIVE TO SUBJECTS WITHOUT HEPATIC IMPAIRMENT

Conditions
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Hepatic Impairment

Intervention / Treatment
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* Drug: PF-05221304


Participation Criteria
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Eligibility Criteria
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Key Exclusion Criteria: All subjects - Adults <18 years of age and >70 years of age BMI < 17.5 and > 35.4 kg/m2 HIV positive Conditions that affect drug absorption Positive breath alcohol test Healthy/ those without hepatic impairment - Known or suspected hepatic impairment Evidence of Hepatitis B or C On any chronic medications Those with varying degrees of hepatic impairment - Not meeting Classification A, B, or C of hepatic impairment based on Child-Pugh Classification Evidence of Hepatic carcinoma or hepatorenal syndrome or limited predicted life expectancy Recent GI bleed Moderate or severe renal impairment Hepatic encephalopathy Grade 3 or higher

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1_Without impairment<br>Single, 25 mg dose of PF-05221304 | Drug: PF-05221304<br>* 25 mg dose<br>* Other names: experimental drug;|
| Experimental: Cohort 2_Mild impairment<br>Single, 25 mg dose of PF-05221304 | Drug: PF-05221304<br>* 25 mg dose<br>* Other names: experimental drug;|
| Experimental: Cohort 3_Moderate impairment<br>Single, 25 mg dose of PF-05221304 | Drug: PF-05221304<br>* 25 mg dose<br>* Other names: experimental drug;|
| Experimental: Cohort 4_Severe impairment<br>Single, 25 mg dose of PF-05221304 | Drug: PF-05221304<br>* 25 mg dose<br>* Other names: experimental drug;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of PF-05221304 | Cmax was observed directly from data. | 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose | 
| Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-05221304 | AUCinf was calculated by AUClast + (Clast*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. | 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose | 
| Fraction Unbound (fu) of PF-05221304 | fu was the fraction of PF-05221304 unbound in plasma. fu was calculated based on the post-dialysis plasma concentrations, post-dialysis buffer concentrations, collected post-dialysis plasma and post-dialysis buffer sample volume (assuming no volume shift prior to and after dialysis), and the total plasma concentrations. | 4 hours postdose | 
| Unbound Cmax (Cmax,u) of PF-05221304 | Cmax,u was calculated by fu*Cmax. | 4 hours postdose | 
| Unbound AUCinf (AUCinf,u) of PF-05221304 | AUCinf,u was calculated by fu*AUCinf. | 4 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Reach Maximum Plasma Concentration (Tmax) of PF-05221304 | Tmax was observed directly from data as time of first occurrence. | 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose | 
| Area Under Concentration Time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) of PF-05221304 | AUClast was calculated by linear/Log trapezoidal method. | 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose | 
| Unbound AUClast ( AUClast,u) of PF-05221304 | AUClast,u was calculated by fu*AUClast. | 4 hours postdose | 
| Apparent Clearance After Oral Dose (CL/F) of PF-05221304 | CL/F was calculated by Dose/AUCinf. | 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose | 
| Unbound CL/F (CLu/F) of PF-05221304 | CLu/F was calculated by fu*CL/F. | 4 hours postdose | 
| Apparent Volume of Distribution After Oral Dose (Vz/F) of PF-05221304 | Vz/F was calculated by Dose/(AUCinf*kel). kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. | 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose | 
| Unbound Vz/F (Vz,u/F) of PF-05221304 | Vz,u/F was calculated by fu*Vz/F. | 4 hours postdose | 
| Terminal Half-Life ( t½) of PF-05221304 | t1/2 was calculated by loge(2)/kel. | 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) was any untoward medical occurrence in a study participant administered a product or medical device; the event did not need to have a causal relationship with the treatment or usage. A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and AEs. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Number of participants with both all-causality and treatment-related TEAEs are presented below. | Approximately 30 days | 
| Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)-Hematology | Hematology evaluation included: hemoglobin, hematocrit, erythrocytes, reticulocytes, erythrocyte mean corpuscular volume, erythrocyte mean corpuscular hemoglobin concentration (MCHC), erythrocyte mean corpuscular hemoglobin, platelets, leukocytes, lymphocytes, neutrophils, basophils, eosinophils, monocytes, activated partial thromboplastin time and prothrombin time. | 7 days | 
| Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)-Clinical Chemistry | Clinical chemistry evaluation included: bilirubin, direct/indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase , alkaline phosphatase, protein, albumin, blood urea nitrogen, creatinine, urate, sodium, potassium, chloride, calcium, phosphate, bicarbonate, creatine kinase, and fasting glucose. | 7 days | 
| Number of Paticipants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)-Urinalysis | Urinalysis evaluation included: scalar urine glucose, scalar ketones, scalar urine protein, scalar urine hemoglobin, scalar urobilinogen, scalar urine bilirubin, scalar nitrite, scalar leukocyte esterase, urine erythrocytes, urine leukocytes, hyaline casts, and scalar bacteria. | 7 days | 
| Number of Participants With Clinical Significant Findings in Vital Signs | Vital signs evaluation included: sitting systolic and diastolic blood pressure (BP), and sitting pulse rate. Clinically significant findings in vital signs were determined by the investigator. | 7 days | 
| Number of Participants With Clinically Significant Findings in Electrocardiogram (ECG) Data | ECG evaluation included: PR interval, time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization (QRS interval), time between the start of the Q wave and the end of the T wave in the heart's electrical cycle (QT interval), QT interval corrected for heart rate using Fridericia's formula (QTcF interval), and heart rate. Clinically significant findings in ECG data were determined by the investigator. | 7 days |