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

Pfizer24 enrolled

Overview

Hepatic impairment PK study

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

Hepatic Impairment

Interventions

PF-05221304DRUG

25 mg dose

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (6)

Orlando Clinical Research Center

Orlando, Florida, United States

Pfizer Clinical Research Unit

Brussels, Belgium

Pharmaceutical Research Associates CZ, s.r.o.

Prague, Czechia

Nemocnice Na Bulovce

Prague, Czechia

Outcomes

Primary Outcomes

Maximum Plasma Concentration (Cmax) of PF-05221304

Cmax was observed directly from data.

Time frame: 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.

Time frame: 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.

Time frame: 4 hours postdose

Unbound Cmax (Cmax,u) of PF-05221304

Cmax,u was calculated by fu\*Cmax.

Time frame: 4 hours postdose

Unbound AUCinf (AUCinf,u) of PF-05221304

AUCinf,u was calculated by fu\*AUCinf.

Time frame: 4 hours postdose

Secondary Outcomes

Time to Reach Maximum Plasma Concentration (Tmax) of PF-05221304

Tmax was observed directly from data as time of first occurrence.

Data from ClinicalTrials.gov

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Summit Clinical Research s.r.o.

Bratislava, Slovakia

Univerzitná Nemocnica Bratislava

Bratislava, Slovakia

Time frame: 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.

Time frame: 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.

Time frame: 4 hours postdose

Apparent Clearance After Oral Dose (CL/F) of PF-05221304

CL/F was calculated by Dose/AUCinf.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 4 hours postdose

Terminal Half-Life ( t½) of PF-05221304

t1/2 was calculated by loge(2)/kel.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 7 days