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

• ClinicalTrials.gov Identifier: NCT03309202
• Recruitment Status: Completed
• First Posted: October 13, 2017
• Results First Posted: August 8, 2019
• Last Update Posted: August 8, 2019
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

Brief Summary:

Hepatic impairment PK study

Condition or disease	Intervention/treatment	Phase
Hepatic Impairment	Drug: PF-05221304	Phase 1

Detailed Description:

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: 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
• Actual Study Start Date: December 19, 2017
• Actual Primary Completion Date: June 26, 2018
• Actual Study Completion Date: July 18, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1_Without impairment; Single, 25 mg dose of PF-05221304	Drug: PF-05221304; 25 mg dose; Other Name: experimental drug
Experimental: Cohort 2_Mild impairment; Single, 25 mg dose of PF-05221304	Drug: PF-05221304; 25 mg dose; Other Name: experimental drug
Experimental: Cohort 3_Moderate impairment; Single, 25 mg dose of PF-05221304	Drug: PF-05221304; 25 mg dose; Other Name: experimental drug
Experimental: Cohort 4_Severe impairment; Single, 25 mg dose of PF-05221304	Drug: PF-05221304; 25 mg dose; Other Name: experimental drug

Outcome Measures

Primary Outcome Measures :

1. Maximum Plasma Concentration (Cmax) of PF-05221304 [ Time Frame: 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose ]
   Cmax was observed directly from data.
2. Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-05221304 [ Time Frame: 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose ]
   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.
3. Fraction Unbound (fu) of PF-05221304 [ Time Frame: 4 hours postdose ]
   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. Unbound Cmax (Cmax,u) of PF-05221304 [ Time Frame: 4 hours postdose ]
   Cmax,u was calculated by fu*Cmax.
5. Unbound AUCinf (AUCinf,u) of PF-05221304 [ Time Frame: 4 hours postdose ]
   AUCinf,u was calculated by fu*AUCinf.

Secondary Outcome Measures :

1. Time to Reach Maximum Plasma Concentration (Tmax) of PF-05221304 [ Time Frame: 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose ]
   Tmax was observed directly from data as time of first occurrence.
2. Area Under Concentration Time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) of PF-05221304 [ Time Frame: 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose ]
   AUClast was calculated by linear/Log trapezoidal method.
3. Unbound AUClast ( AUClast,u) of PF-05221304 [ Time Frame: 4 hours postdose ]
   AUClast,u was calculated by fu*AUClast.
4. Apparent Clearance After Oral Dose (CL/F) of PF-05221304 [ Time Frame: 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose ]
   CL/F was calculated by Dose/AUCinf.
5. Unbound CL/F (CLu/F) of PF-05221304 [ Time Frame: 4 hours postdose ]
   CLu/F was calculated by fu*CL/F.
6. Apparent Volume of Distribution After Oral Dose (Vz/F) of PF-05221304 [ Time Frame: 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose ]
   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.
7. Unbound Vz/F (Vz,u/F) of PF-05221304 [ Time Frame: 4 hours postdose ]
   Vz,u/F was calculated by fu*Vz/F.
8. Terminal Half-Life ( t½) of PF-05221304 [ Time Frame: 0, 1, 2, 3, 4, 5, 8, 10, 16, 24, 36, 48, 72, 96, 120, 144 hours postdose ]
   t1/2 was calculated by loge(2)/kel.
9. Number of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Approximately 30 days ]
   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.
10. Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)-Hematology [ Time Frame: 7 days ]
    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.
11. Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)-Clinical Chemistry [ Time Frame: 7 days ]
    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.
12. Number of Paticipants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)-Urinalysis [ Time Frame: 7 days ]
    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.
13. Number of Participants With Clinical Significant Findings in Vital Signs [ Time Frame: 7 days ]
    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.
14. Number of Participants With Clinically Significant Findings in Electrocardiogram (ECG) Data [ Time Frame: 7 days ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

United States, Florida

Orlando Clinical Research Center

Orlando, Florida, United States, 32809

Belgium

Pfizer Clinical Research Unit

Brussels, Belgium, B-1070

Czechia

Pharmaceutical Research Associates CZ, s.r.o.

Praha 7, Czechia, 170 00

Nemocnice Na Bulovce

Praha 8, Czechia, 180 81

Slovakia

Summit Clinical Research s.r.o.

Bratislava, Slovakia, 83101

Univerzitná Nemocnica Bratislava

Bratislava, Slovakia, 83305

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

  Study Documents (Full-Text)

Documents provided by Pfizer:

Statistical Analysis Plan  [PDF] April 29, 2019

Study Protocol  [PDF] September 18, 2017

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

To obtain contact information for a study center near you, click here. 

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT03309202
• Other Study ID Numbers: C1171006; 2017-003034-86 ( EudraCT Number )
• First Posted: October 13, 2017
• Results First Posted: August 8, 2019
• Last Update Posted: August 8, 2019
• Last Verified: June 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Liver Diseases; Digestive System Diseases