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

• ClinicalTrials.gov Identifier: NCT02252731
• Recruitment Status: Completed
• First Posted: September 30, 2014
• Last Update Posted: September 30, 2014
• Sponsor: Astellas Pharma Europe B.V.
• Collaborator: FibroGen
• Information provided by (Responsible Party): Astellas Pharma Inc ( Astellas Pharma Europe B.V. )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Pharmacokinetics of FG-4592; Healthy Subjects	Drug: Warfarin; Drug: FG-4592	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 22 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• 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 Start Date: September 2013
• Actual Primary Completion Date: November 2013
• Actual Study Completion Date: November 2013

Arms and Interventions

Arm	Intervention/treatment
Experimental: warfarin and FG-4592; Single dose of warfarin and Multiple doses of FG-4592 in combination with a single dose of warfarin	Drug: Warfarin; Oral; Other Name: Coumadin®; Drug: FG-4592; Oral; Other Names: ASP1517,; roxadustat

Outcome Measures

Primary Outcome Measures :

1. 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) [ Time Frame: Period 1 (Day 1 to Day 8); Period 2 (Day 7 to Day 16) ]
2. PK of S-warfarin and R-warfarin in plasma measured by maximum concentration (Cmax) [ Time Frame: Period 1 (Day 1 to Day 8); Period 2 (Day 7 to Day 16) ]

Secondary Outcome Measures :

1. PK profile of S-warfarin and R-warfarin in plasma [ Time Frame: Period 1 (Day 1 to Day 8); Period 2 (Day 7 to Day 16) ]
   area under the concentration-time curve from the time of dosing to the last measurable concentration (Clast) (AUClast), unbound AUC from the time of dosing to Clast (AUClast,u), AUC from the time of dosing extrapolated to time infinity (AUCinf), unbound AUC extrapolated to infinity (AUCinf,u), maximum unbound plasma concentration (Cmax,u), apparent total body clearance after extra-vascular dosing (CL/F), unbound apparent total body clearance after extravascular dosing (CLu/F), fraction unbound (fu), time interval between the time of dosing and the first measurable concentration (tlag), time of the maximum concentration (tmax), terminal elimination half-life (t1/2), apparent volume of distribution during the terminal elimination phase after single extravascular dosing (Vz/F), unbound apparent volume of distribution during terminal phase after oral administration (Vz,u/F)
2. PK profile of FG-4592 in plasma [ Time Frame: Period 2 (Day 1 to Day 15) ]
   AUC from time point 0 to time point 24 hours (AUC0-24h), AUClast, AUCinf , Cmax, concentration at pre-dose for repeated dosing (Ctrough), tmax, t1/2, CL/F, and Vz/F
3. PK profile of FG-4592 in urine [ Time Frame: Period 2 (Day 7 to Day 8) ]
   renal clearance (CLR), unbound CLR from time point 0 to 24 hours (CLR,0-24h), cumulative amount of drug excreted unchanged into urine from time of dosing extrapolated to time infinity (Aeinf), percent of drug excreted unchanged into urine from time of dosing extrapolated to time infinity in percent of dose (Aeinf%), cumulative amount of drug excreted unchanged into urine, from time of dosing up to the collection time of the last measurable concentration (Aelast), percent of drug excreted into urine from time of dosing up to the collection time of the last measurable concentration in percent of dose (Aelast%), cumulative amount of drug excreted unchanged into urine, from time of dosing up to the collection time of 24 hours (Ae0 24h), cumulative amount of drug excreted unchanged into urine, from time of dosing up to the collection time of 24 hours in percent of dose (Ae0-24h%)
4. Pharmacodynamics profile of warfarin in plasma [ Time Frame: Period 1 Day 1 to to ESV (5 to 9 days after the last protocol defined assessment of Period 2 (or after early withdrawal)) ]
   area under the Prothrombin Time (PT)-time curve from the time of dosing until the last sample collected (AUCPT,last), maximal PT (PTmax), time to reach PTmax (tPT,max), area under the International Normalized Ratio (INR)-time curve from the time of dosing until the last sample collected (AUCINR,last), maximal INR after Drug Administration (INRmax), time to reach the INRmax (tINR,max)
5. Safety profile [ Time Frame: 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)) ]
   Safety profile includes Adverse Events (AEs), vital signs, physical examination, laboratory tests, electrocardiogram (ECG)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

Germany

Parexel International GmbH

Berlin, Germany, 14050

Sponsors and Collaborators

Astellas Pharma Europe B.V.

FibroGen

Investigators

• Study Director: Study Physician; Astellas Pharma Europe B.V.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Astellas Pharma Europe B.V.
• ClinicalTrials.gov Identifier: NCT02252731 History of Changes
• Other Study ID Numbers: 1517-CL-0509; 2013-001043-31 ( EudraCT Number )
• First Posted: September 30, 2014
• Last Update Posted: September 30, 2014
• Last Verified: September 2014

Keywords provided by Astellas Pharma Inc ( Astellas Pharma Europe B.V. ):

Phase I; FG-4592; Warfarin; Pharmacokinetics; Pharmacodynamics

Additional relevant MeSH terms:

Warfarin; Anticoagulants