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

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

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.

Study Overview

• Status: Completed
• Conditions: Drug Interaction Potentiation
• Intervention / Treatment: Drug: vadadustat; Drug: Cyclosporins; Drug: Probenecid; Drug: Rifampin

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 Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Québec City, Quebec, Canada, G1P A02
      • inVentiv Health Clinique Inc.

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Akebia Therapeutics
• Investigators: Study Director: Akebia Inc, Sponsor GmbH

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2018
• Primary Completion (Actual): August 15, 2018
• Study Completion (Actual): August 15, 2018

Study Registration Dates

• First Submitted: December 27, 2018
• First Submitted That Met QC Criteria: January 9, 2019
• First Posted (Actual): January 11, 2019

Study Record Updates

• Last Update Posted (Actual): March 22, 2019
• Last Update Submitted That Met QC Criteria: March 20, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Healthy volunteers; vadadustat; drug interactions
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Antifungal Agents; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Gout Suppressants; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Calcineurin Inhibitors; Renal Agents; Uricosuric Agents; Rifampin; Cyclosporine; Cyclosporins; Probenecid
• Other Study ID Numbers: AKB-6548-CI-0029

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No