Drug-Drug Interaction Study of Vadadustat With Digoxin, Adefovir and Furosemide

Study Overview
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Brief Summary
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This is a Phase 1, open-label, 3-arm, fixed sequence, study to evaluate vadadustat as a perpetrator of drug-drug interactions (DDIs) with digoxin, adefovir and furosemide in healthy male and female subjects.

Detailed Description
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This is a Phase 1, open-label, 3-arm, fixed sequence, study to evaluate vadadustat as a perpetrator of drug-drug interactions (DDIs) with digoxin, adefovir and furosemide in healthy male and female subjects. Unique subjects will be enrolled into each arm of the study and enrollment will be sequential. The first 20 subjects confirmed to be eligible will be assigned to Arm 1 (digoxin), the next 16 subjects will be assigned to Arm 2 (adefovir) and the next 22 subjects will be assigned to Arm 3 (furosemide). Blood samples for PK analysis will be collected at pre-defined timepoints for each arm throughout the study. Subjects will be on study for up to 80 days, including a 28-day screening period, 7-21 day in clinic period, and a 30-day follow up period post last dose.

Official Title
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A Phase 1 Open-label, Three Arm Study in Healthy Adult Volunteers to Assess Vadadustat as a Perpetrator in Drug-Drug-Interactions With Digoxin, Adefovir and Furosemide

Conditions
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Drug Interaction Potentiation

Intervention / Treatment
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* Drug: Vadadustat
* Drug: Furosemide
* Drug: Adefovir
* Drug: Digoxin


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. 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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Each arm has fixed sequence design. Arm 1 (n = 20): Digoxin 0.5 mg alone, vadadustat 600 mg alone and digoxin + vadadustat Arm 2 (n = 16): adefovir 10mg alone, vadadustat 600 mg QD alone and adefovir + vadadustat Arm 3 (n=22) : furosemide 40mg alone, vadadustat 600 mg QD alone, and furosemide + vadadustat
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vadadustat, digoxin<br>Arm 1: Subjects will receive a single oral dose of digoxin 0.5 mg alone, followed by a washout period and repeat doses of vadadustat 600 mg QD alone and in combination with a single dose of digoxin 0.5 mg. | Drug: Vadadustat<br>* Oral dose 600 mg<br>* Other names: AKB 6548;Drug: Digoxin<br>* Oral Digoxin<br>|
| Experimental: Vadadustat, adefovir<br>Arm 2: Subjects will receive a single dose of oral adefovir 10 mg alone, followed by a washout period and repeat doses of vadadustat 600 mg QD alone and in combination with a single dose of adefovir. | Drug: Vadadustat<br>* Oral dose 600 mg<br>* Other names: AKB 6548;Drug: Adefovir<br>* Oral Adefovir<br>|
| Experimental: Vadadustat, Furosemide<br>Arm 3: Subjects will receive a single dose of oral furosemide 40 mg alone, followed by a washout period and repeat doses of vadadustat 600 mg QD alone, and in combination with a single dose of furosemide 40 mg. | Drug: Vadadustat<br>* Oral dose 600 mg<br>* Other names: AKB 6548;Drug: Furosemide<br>* Oral Furosemide<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) for digoxin, adefovir and furosemide |  | Up to 12 Weeks | 
| Area under plasma concentration-time curve from 0 to infinity (AUCinf) for digoxin, adefovir and furosemide |  | Up to 12 Weeks | 
| Maximum observed plasma concentration (Cmax) for digoxin, adefovir and furosemide |  | Up to 12 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to maximum observed plasma concentration (Tmax) for digoxin, adefovir and furosemide |  | Up to 12 Weeks | 
| Elimination rate constant (Kel) for digoxin, adefovir and furosemide |  | Up to 12 Weeks | 
| Terminal half-life (t½) for digoxin, adefovir and furosemide |  | Up to 12 Weeks | 
| Apparent total body clearance (CL/F) for digoxin, adefovir and furosemide |  | Up to 12 Weeks | 
| Percent of extrapolated area under the curve from time t to infinity (%AUCextrap) for digoxin, adefovir and furosemide |  | Up to 12 Weeks | 
| Reporting of Treatment Emergent Adverse Events (TEAEs) as reported by study subjects |  | Up to 12 Weeks | 

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