A Study to Investigate the Exposure and Safety and Tolerability of a Single Dose of FG-4592 in Subjects With Moderately Diminished Liver Function Compared to Those With Normal Liver Function

A Phase 1, Non-randomized, Open-label, Single-dose Study to Investigate the Pharmacokinetics, Safety and Tolerability of FG-4592 in Subjects With Moderate Hepatic Impairment and Healthy Subjects With Normal Hepatic Function

The effect of moderately diminished liver function on the exposure, safety and tolerability of a single dose of FG-4592 is studied in male and female subjects. The results are compared to the data gained from subjects with normal liver function.

Study Overview

• Status: Completed
• Conditions: Hepatic Insufficiency; Healthy Subjects; PK of FG-4592
• Intervention / Treatment: Drug: FG-4592

Detailed Description

The effect of moderate hepatic impairment on the pharmacokinetics (PK), safety and tolerability of a single dose of FG-4592 in male and female subjects is investigated. Data obtained from these subjects are compared to data from BMI-, age- and sex-matched subjects with normal hepatic function. Both groups consist of 8 subjects.

Screening takes place from Days -22 to -2 before admission to the clinical unit on Day -1. Administration of the trial medication takes place on Day 1 under fasted conditions. Healthy subjects are discharged on Day 5 and subjects with moderate hepatic impairment on Day 7, if there is no reason to extend the stay. An end-of-study visit (ESV) takes place 5 to 9 days after (early) discharge.

Safety assessments are performed throughout the study.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• Bulgaria
  • Sofia, Bulgaria
    • COMAC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Both healthy subjects and subjects with moderate hepatic impairment:

• Independent Ethics Committee (IEC)-approved written Informed Consent and privacy language as per national regulations must be obtained from the subject prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
• Male subjects and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of 2 forms of birth control (1 of which must be a barrier method) starting at screening and continuing throughout the study period and for 90 days after the study drug administration.

In addition, subjects with moderate hepatic impairment must also meet the following inclusion criteria:

• Subject has Child-Pugh classification Class B (moderate, 7 to 9 points) liver function impairment [screening].

Exclusion Criteria:

Both healthy subjects and subjects with moderate hepatic impairment:

• Female subject who has been pregnant within 6 months prior to screening or breastfeeding within 3 months before screening.
• Subject has a known or suspected hypersensitivity to FG-4592, or any components of the formulation used.

In addition, healthy subjects must also NOT meet the following exclusion criteria:

• Subject has any of the liver function tests (LFT) (Aspartate Aminotransferase [AST], Alanine Aminotransferase [ALT], Alkaline Phosphatase [ALP], Gamma Glutamyl Transferase [GGT], Total Bilirubin [TBL] above the upper limit of normal (ULN). In such a case the assessment may be repeated once [Day-1].

In addition, subjects with moderate hepatic impairment must also NOT meet the following exclusion criteria:

• Subject had a previous liver transplantation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1: FG-4592 in subjects with moderate hepatic impairment	Drug: FG-4592; Oral; Other Names: ASP1517,; roxadustat
Experimental: 2: FG-4592 in healthy subjects	Drug: FG-4592; Oral; Other Names: ASP1517,; roxadustat

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetic parameter of FG-4592 in plasma as measured by area under the concentration-time curve (AUC) extrapolated to infinity (AUCinf)	Days 1 to 5 (Day 7 for hepatic impaired subjects)
Pharmacokinetic parameter of FG-4592 in plasma as measured by maximum concentration (Cmax)	Days 1 to 5 (Day 7 for hepatic impaired subjects)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic profile of FG-4592 in plasma	AUC up to last quantifiable concentration (AUClast), AUC from 0 up to last quantifiable concentration based on unbound plasma concentration (AUClast,u), AUC from time point 0 to time point 24 hours (AUC0-24h), AUC from time point 0 to time point 24 hours based on unbound plasma concentration (AUC0-24h,u), unbound AUC extrapolated to infinity (AUCinf,u), unbound maximum concentration (observed) (Cmax,u), apparent total systemic clearance after extra-vascular dosing (CL/F), plasma clearance over bioavailability ratio based on unbound plasma (CLu/F), fraction unbound (fu), lag-time (time delay between drug administration and first observed concentration above the Limit of Quantification (LOQ) in plasma) (tlag), time to attain Cmax (tmax), apparent terminal elimination half-life (t1/2), apparent volume of distribution during terminal phase after oral administration (Vz/F), unbound apparent volume of distribution during terminal phase after oral administration (Vz,u/F)	Days 1 to 5 (Day 7 for hepatic impaired subjects)
Pharmacokinetic profile of FG-4592 in urine	renal clearance (CLR), renal clearance based on unbound concentration (CLR,u), renal clearance from time point 0 to 24 hours (CLR,0-24h), renal clearance from time point 0 to 24 hours based on unbound concentration (CLR,u 0-24h), amount of unchanged drug excreted into urine from time point 0 to infinity (Aeinf), amount of unchanged drug excreted into urine from time point 0 to infinity, percentage of dose (Aeinf%), amount of unchanged drug excreted into urine until the last observation time point (Aelast), amount of unchanged drug excreted into urine until the last observation time, percentage of dose (Aelast%), amount of drug excreted into urine from time point 0 to time point 24 hours (Ae0-24h), amount of drug excreted into urine from time point 0 to time point 24 hours, percentage of dose (Ae0-24h%)	Days 1 to 5 (Day 7 for hepatic impaired subjects)
Erythropoietin in plasma	maximum achievable pharmacologic effect (Emax), area under the concentration-time curve from 0 up to last quantifiable concentration based on EPO concentration (AUCE,last), tmax	Days 1 to 5 (Day 7 for hepatic impaired subjects)
Safety and tolerability of FG-4592	Nature, frequency and severity of adverse events (AEs), vital signs, safety laboratory tests, electrocardiogram	Screening (Days -22 to -2) to ESV (5 to 9 days after (early) discharge)

Collaborators and Investigators

• Sponsor: Astellas Pharma Europe B.V.
• Collaborators: FibroGen

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: June 9, 2014
• First Submitted That Met QC Criteria: June 9, 2014
• First Posted (Estimate): June 11, 2014

Study Record Updates

• Last Update Posted (Estimate): June 11, 2014
• Last Update Submitted That Met QC Criteria: June 9, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: Phase 1; Single dose; FG-4592; Moderate hepatic impairment
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure; Hepatic Insufficiency
• Other Study ID Numbers: 1517-CL-0513; 2013-001533-41 (EudraCT Number)