Drug-Drug Interaction Study of Vadadustat With Cyclosporine, Probenecid and Rifampin

Sponsor

Akebia Therapeutics (Industry)

Overall Status

Completed

CT.gov ID

NCT03801746

Collaborator

(none)

Enrollment

Location

Arms

Actual Duration (Days)

46.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a Phase 1, two-part, open-label study to evaluate the interaction of cyclosporine, probenecid, and rifampin as perpetrators with vadadustat (victim) in healthy male and female subjects.

Condition or Disease	Intervention/Treatment	Phase
Drug Interaction Potentiation	Drug: vadadustat Drug: Rifampin Drug: Probenecid Drug: Cyclosporins	Phase 1

Detailed Description

This is a Phase 1, two-part, open-label study to evaluate the interaction of cyclosporine, probenecid, and rifampin as perpetrators with vadadustat (victim) in healthy male and female subjects. Part 1 consists of 2 arms (cyclosporine and probenecid) and Part 2 consists of 1 arm (rifampin). Twenty (20) unique subjects will be enrolled into each study arm. The PK and safety/tolerability data from Part 1 Arm 1 (cyclosporine) will determine if Part 2 (rifampin) will proceed. Subjects will be on study for up to 72 days, including a 28-day screening period, 6-10 day clinic period, and a 30-day follow-up period post last dose. Blood and/or urine samples for PK analysis will be collected at pre-defined timepoints throughout the study.

Study Design

Study Type:

Interventional

Actual Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

This is a 2 part study. Part 1 Arm 1 is a cross over design to assess the drug-drug interactions of cyclosporine with vadadustat. Part 1 Arm 2 is a fixed sequence design to assess the drug-drug interactions of probenecid with vadadustat. Part 2 is a crossover design to assess the drug-drug interaction of rifampin with vadadustatThis is a 2 part study. Part 1 Arm 1 is a cross over design to assess the drug-drug interactions of cyclosporine with vadadustat. Part 1 Arm 2 is a fixed sequence design to assess the drug-drug interactions of probenecid with vadadustat. Part 2 is a crossover design to assess the drug-drug interaction of rifampin with vadadustat

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

A Phase 1, Two-Part, Open-label Study in Healthy Adult Volunteers to Assess a Single Dose of Vadadustat as a Victim in Drug-Drug Interactions With Cyclosporine, Probenecid and Rifampin

Actual Study Start Date :

Jul 20, 2018

Actual Primary Completion Date :

Aug 15, 2018

Actual Study Completion Date :

Aug 15, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vadadustat, Cyclosporine Part 1: Arm 1: Subjects will receive vadadustat 300 mg alone and vadadustat 300 mg in combination with oral cyclosporine 500 mg in a crossover design	Drug: vadadustat Oral dose 300 mg Other Names: AKB 6548 Drug: Cyclosporins Oral Cyclosporine
Experimental: Vadadustat; Probenecid Part 1: Arm 2: Subjects will receive vadadustat 300 mg alone and vadadustat 300 mg in combination with oral Probenecid 500 mg Q12h in a fixed sequence design	Drug: vadadustat Oral dose 300 mg Other Names: AKB 6548 Drug: Probenecid Oral Probenecid
Experimental: Vadadustat and Rifampin Part 2: Subjects will receive vadadustat 300 mg alone and vadadustat 300 mg in combination with IV rifampin 600 mg in a cross-over design	Drug: vadadustat Oral dose 300 mg Other Names: AKB 6548 Drug: Rifampin IV Rifampin

Arm

Intervention/Treatment

Experimental: Vadadustat, Cyclosporine

Part 1: Arm 1: Subjects will receive vadadustat 300 mg alone and vadadustat 300 mg in combination with oral cyclosporine 500 mg in a crossover design

Drug: vadadustat

Oral dose 300 mg

Other Names:

AKB 6548

Drug: Cyclosporins

Oral Cyclosporine

Experimental: Vadadustat; Probenecid

Part 1: Arm 2: Subjects will receive vadadustat 300 mg alone and vadadustat 300 mg in combination with oral Probenecid 500 mg Q12h in a fixed sequence design

Drug: vadadustat

Oral dose 300 mg

Other Names:

AKB 6548

Drug: Probenecid

Oral Probenecid

Experimental: Vadadustat and Rifampin

Part 2: Subjects will receive vadadustat 300 mg alone and vadadustat 300 mg in combination with IV rifampin 600 mg in a cross-over design

Drug: vadadustat

Oral dose 300 mg

Other Names:

AKB 6548

Drug: Rifampin

IV Rifampin

Outcome Measures

Primary Outcome Measures

Area under plasma concentration-time curve from 0 to last quantifiable concentration (AUClast) of vadadustat [Up to 10 weeks]
Area under plasma concentration-time curve from 0 to infinity (AUCinf) of vadadustat [Up to 10 weeks]
Maximum observed plasma concentration (Cmax) of vadadustat [Up to 10 weeks]

Secondary Outcome Measures

Time to maximum observed plasma concentration (Tmax) of vadadustat [Up to 10 weeks]
Elimination rate constant (Kel) of vadadustat [Up to 10 weeks]
Terminal half-life (t½) of vadadustat [Up to 10 weeks]
Apparent total body clearance (CL/F) of vadadustat [Up to 10 weeks]
Percent of extrapolated area under the curve from time t to infinity (%AUCextrap) of vadadustat [Up to 10 weeks]
Renal clearance (CLr) of vadadustat and vadadustat 1-O-glucuronide excretion in urine for Part 1 Arm 2 (Probenecid) only [Up to 10 weeks]
Cumulative amount excreted (Ae0-t) of vadadustat and vadadustat 1-O-glucuronide in urine for Part 1 Arm 2 (Probenecid) only [Up to 10 weeks]
Fraction (%) of the dose excreted (Fe%0-t) for Part 1 Arm 2 (Probenecid) only of vadadustat and vadadustat 1-O-glucuronide excretion in urine [Up to 10 weeks]
Area under plasma concentration-time curve from 0 to last quantifiable concentration (AUClast) of vadadustat metabolites [Up to 10 weeks]
Area under plasma concentration-time curve from 0 to infinity (AUCinf) of vadadustat metabolites [Up to 10 weeks]
Maximum observed plasma concentration (Cmax) of vadadustat metabolites [Up to 10 weeks]
Reporting of treatment emergent adverse events as reported by the study subject [Up to 10 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Healthy Male or female between 18 and 55 years of age, inclusive, at time of informed consent
Body mass index between 18.0 and 30.0 kg/m2, with a minimum body weight of 45 kg for females and 50 kg for males, inclusive.

Exclusion Criteria:

Current or past clinically significant history of cardiovascular, cerebrovascular, pulmonary, gastrointestinal, hematologic, renal, hepatic, immunologic, metabolic, urologic, neurologic, dermatologic, psychiatric, or other major disease. History of cancer (except treated non-melanoma skin cancer) or history of chemotherapy use within 5 years prior to Screening; History of latent or active tuberculosis (TB).
Positive test results for human immunodeficiency virus (HIV) antibody; Positive test results of hepatitis B surface antigen (HBsAg), or positive hepatitis C virus antibody (HCVab) within 3 months prior to screening , or positive test results for human immunodeficiency virus antibody (HIVab) at Screening.
Taking any prescription medication or over the counter multi-vitamin supplement, or any non-prescription products (including herbal-containing preparations but excluding acetaminophen) within 14 days prior to Day -1.