Clinical trial NCT02252731: A Study to Evaluate the Effects of Multiple Doses of FG-4592 on the Exposure, Safety and Tolerability and Effect of Warfarin in Healthy Subjects
Official title: A Phase 1, Open-label, One-sequence Crossover Study to Evaluate the Effect of Multiple Doses of FG 4592 on the Pharmacokinetics of Warfarin in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pharmacokinetics of FG-4592
Healthy Subjects
Keywords: Phase I
FG-4592
Warfarin
Pharmacokinetics
Pharmacodynamics
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
Collaborators: name: FibroGen
First posted: 2014-09-30
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: This study will determine the effect of multiple doses of FG-4592 on the pharmacokinetics (PK) of a single dose of warfarin. It will evaluate the safety and tolerability of warfarin alone and in combination with multiple doses of FG-4592, and will evaluate the effect of multiple doses of FG-4592 on the pharmacodynamics (PD) of warfarin.

Detailed description: The study consists of 2 periods, separated by a washout period (a minimum of 14 days after warfarin dosing on Day 1, Period 1). Screening takes place from Day -22 to Day -2.

Subjects are admitted to the clinical unit on Day -1 of Period 1. On Day 1 of the first period, subjects receive a single oral dose of warfarin. After completion of all assessments on Day 8, subjects are discharged from the clinical unit on the condition that there are no medical reasons for a prolonged stay. They return to the clinical unit on Day -1 of the second period, after the washout period.

In Period 2, the subjects receive multiple doses of FG 4592. On Day 7 of Period 2, FG 4592 is given concomitantly with warfarin. After completion of all assessments on Day 16 of Period 2, subjects are discharged from the clinic on the condition that there are no medical reasons for a prolonged stay. The subjects return for an End of Study Visit (ESV) 5 to 9 days after the last assessment of Period 2 (or after early withdrawal).

Safety assessments are performed throughout the study. Blood and urine samples are collected for PK and PD assessments.

Eligibility criteria: Inclusion Criteria:

* Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control.
* Male subject must not donate sperm starting at screening and throughout the study period and for 90 days after the final study drug administration.
* Female subject must be either of non-childbearing potential or, if of childbearing potential, must have a negative pregnancy test at screening and Day -1 and must use two forms of birth control.
* Female subject must not donate ova starting at screening and throughout the study period and for 28 days after the final study drug administration.

Exclusion Criteria:

* Subject has a known or suspected hypersensitivity to FG 4592, warfarin, or any components of the formulations used.
* Subject has/had febrile illness or symptomatic, viral, bacterial (including upper respiratory infection), or fungal (non-cutaneous) infection within 1 week prior to admission to the clinical unit \[Day -1\].
* Subject is lactose intolerant.

Primary outcomes:
measure: PK of S-warfarin and R-warfarin in plasma measured by area under the curve from the time of dosing extrapolated to time infinity (AUCinf)
timeFrame: Period 1 (Day 1 to Day 8); Period 2 (Day 7 to Day 16)
measure: PK of S-warfarin and R-warfarin in plasma measured by maximum concentration (Cmax)
timeFrame: Period 1 (Day 1 to Day 8); Period 2 (Day 7 to Day 16)
Secondary outcomes:
measure: PK profile of S-warfarin and R-warfarin in plasma
timeFrame: Period 1 (Day 1 to Day 8); Period 2 (Day 7 to Day 16)
measure: PK profile of FG-4592 in plasma
timeFrame: Period 2 (Day 1 to Day 15)
measure: PK profile of FG-4592 in urine
timeFrame: Period 2 (Day 7 to Day 8)
measure: Pharmacodynamics profile of warfarin in plasma
timeFrame: Period 1 Day 1 to to ESV (5 to 9 days after the last protocol defined assessment of Period 2 (or after early withdrawal))
measure: Safety profile
timeFrame: Screening (Day -22 to Day -2) to ESV (5 to 9 days after the last protocol defined assessment of Period 2 (or after early withdrawal))
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Parexel International GmbH
Study officials:
affiliation: Astellas Pharma Europe B.V.
name: Study Physician
role: STUDY_DIRECTOR
References:
citation: Groenendaal-van de Meent D, den Adel M, Rijnders S, Krebs-Brown A, Kerbusch V, Golor G, Schaddelee M. The Hypoxia-inducible Factor Prolyl-Hydroxylase Inhibitor Roxadustat (FG-4592) and Warfarin in Healthy Volunteers: A Pharmacokinetic and Pharmacodynamic Drug-Drug Interaction Study. Clin Ther. 2016 Apr;38(4):918-28. doi: 10.1016/j.clinthera.2016.02.010. Epub 2016 Mar 4.