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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Drug Interaction Potentiation

Intervention / Treatment
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* Drug: vadadustat
* Drug: Rifampin
* Drug: Probenecid
* Drug: Cyclosporins


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional 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 vadadustat
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vadadustat, Cyclosporine<br>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<br>* Oral dose 300 mg<br>* Other names: AKB 6548;Drug: Cyclosporins<br>* Oral Cyclosporine<br>|
| Experimental: Vadadustat; Probenecid<br>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<br>* Oral dose 300 mg<br>* Other names: AKB 6548;Drug: Probenecid<br>* Oral Probenecid<br>|
| Experimental: Vadadustat and Rifampin<br>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<br>* Oral dose 300 mg<br>* Other names: AKB 6548;Drug: Rifampin<br>* IV Rifampin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy volunteers, vadadustat, drug interactions