Drug-Drug Interaction Study of Vadadustat With Rosuvastatin, Sulfasalazine, Pravastatin, Atorvastatin and Simvastatin

A Phase 1, Three-Part, Open-label Study in Healthy Adult Volunteers to Assess Vadadustat as a Perpetrator in Drug-Drug Interactions With Rosuvastatin, Sulfasalazine, Pravastatin, Atorvastatin and Simvastatin

This is a Phase 1, three-part, open-label study to evaluate vadadustat as a perpetrator in drug-drug interactions with rosuvastatin, sulfasalazine, pravastatin, atorvastatin and simvastatin in healthy male and female subjects.

Study Overview

• Status: Completed
• Conditions: Drug Interaction Potentiation
• Intervention / Treatment: Drug: Vadadustat; Drug: Rosuvastatin; Drug: Pravastatin; Drug: Sulfasalazine; Drug: Simvastatin; Drug: Atorvastatin

Detailed Description

This is a Phase 1, three-part, open-label study to evaluate vadadustat as a perpetrator in drug-drug interactions with rosuvastatin, sulfasalazine, pravastatin, atorvastatin, and simvastatin in healthy male and female subjects. Thirty-four (34) subjects will be enrolled in Part 1 (rosuvastatin) and based on review of the PK and safety/tolerability data, a decision will be made on whether to proceed with Part 2. Part 2 consists of 2 arms (sulfasalazine and pravastatin). Twenty-six (26) subjects will be enrolled into each arm. Part 3 consists of 2 arms (atorvastatin and simvastatin). Twenty-four (24) subjects will be enrolled into each arm after enrollment in Part 2 is completed. Subjects will be in the study for up to 72 days, including a 28-day screening period, 6-14 day in clinic period, and a 30-day follow up period post last dose. Blood samples for PK analysis will be collected at pre-defined time points throughout the study.

• Study Type: Interventional
• Enrollment (Actual): 134
• 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: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• 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; 12. 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: Rosuvastatin, Vadadustat; Part 1: Subjects will receive rosuvastatin 20 mg alone, vadadustat 600 mg alone, followed by rosuvastatin 20 mg in combination with vadadustat 600 mg in a fixed-sequence dosing design.	Drug: Vadadustat; Oral dose of 600 mg QD; Other Names: AKB 6548; Drug: Rosuvastatin; Oral Rosuvastatin
Experimental: Sulfasalazine. Pravastatin, Vadadustat; Part 2, Arm 1: Subjects will receive sulfasalazine 500 mg alone followed by sulfasalazine 500 mg in combination with vadadustat 600 mg once a day in a fixed-sequence dosing design. Part 2, Arm 2: Subjects will receive pravastatin 40 mg alone followed by pravastatin 40 mg in combination with vadadustat 600 mg once a day in a fixed-sequence dosing design.	Drug: Vadadustat; Oral dose of 600 mg QD; Other Names: AKB 6548; Drug: Pravastatin; Oral Pravastatin; Drug: Sulfasalazine; Oral Sulfasalazine
Experimental: Atorvastatin, Simvastatin, Vadadustat; Part 3, Arm 1: Subjects will receive atorvastatin 40 mg alone followed by atorvastatin 40 mg in combination with vadadustat 600 mg once a day in a fixed-sequence dosing design. Part 3, Arm 2: 24 subjects will receive simvastatin 40 mg alone followed by simvastatin 40 mg in combination with vadadustat 600 mg once a day in a fixed-sequence dosing design.	Drug: Vadadustat; Oral dose of 600 mg QD; Other Names: AKB 6548; Drug: Simvastatin; Oral Simvastatin; Drug: Atorvastatin; Oral Atorvastatin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Area under plasma concentration-time curve from time 0 to last quantifiable concentration (AUClast) of rosuvastatin, sulfasalazine, pravastatin and simvastatin	Up to 10 weeks
Area under plasma concentration-time curve from time 0 to infinity (AUCinf) of rosuvastatin, sulfasalazine, pravastatin and simvastatin	Up to 10 weeks
Maximum observed plasma concentration (Cmax) of rosuvastatin. sulfasalazine, pravastatin, atorvastatin and simvastatin	Up to 10 weeks
Area under plasma concentration-time curve (AUCtau) of atorvastatin	Up to 10 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to maximum observed plasma concentration (Tmax) of rosuvastatin, sulfasalazine, pravastatin, atorvastatin, and simvastatin	Up to 10 weeks
Elimination rate constant (Kel) of rosuvastatin, sulfasalazine, pravastatin, atorvastatin, and simvastatin	Up to 10 weeks
Terminal half-life (t½) of rosuvastatin, sulfasalazine, pravastatin, atorvastatin, and simvastatin	Up to 10 weeks
Apparent total body clearance (CL/F) of rosuvastatin, sulfasalazine, pravastatin, atorvastatin, and simvastatin	Up to 10 weeks
Percentage of extrapolated area under the curve from time t to infinity (%AUCextrap or Residual Area) of rosuvastatin, sulfasalazine, pravastatin, atorvastatin, and simvastatin	Up to 10 weeks
Area under plasma concentration-time curve from time 0 to last quantifiable concentration (AUClast) of sulfasalazine metabolites, sulfapyridine and 5-ASA (mesalamine	Up to 10 weeks
Area under plasma concentration-time curve from time 0 to infinity (AUCinf) of sulfasalazine metabolites, sulfapyridine and 5-ASA (mesalamine	Up to 10 weeks
Maximum observed plasma concentration (Cmax) of sulfasalazine metabolites, sulfapyridine and 5-ASA (mesalamine	Up to 10 weeks
Time to maximum observed plasma concentration (Tmax) of sulfasalazine metabolites, sulfapyridine and 5-ASA (mesalamine	Up to 10 weeks
Elimination rate constant (Kel) of sulfasalazine metabolites, sulfapyridine and 5-ASA (mesalamine	Up to 10 weeks
Terminal half-life (t½) of sulfasalazine metabolites, sulfapyridine and 5-ASA (mesalamine	Up to 10 weeks
Area under the plasma concentration-time curve for a dosing interval (AUCtau) of atorvastatin metabolites, o-hydroxyatorvastatin; p-hydroxyatorvastatin	Up to 10 weeks
Maximum observed plasma concentration (Cmax) of atorvastatin metabolites, o-hydroxyatorvastatin; p-hydroxyatorvastatin	Up to 10 weeks
Time to maximum observed plasma concentration (Tmax) of atorvastatin metabolites, o-hydroxyatorvastatin; p-hydroxyatorvastatin	Up to 10 weeks
Area under plasma concentration-time curve from time 0 to last quantifiable concentration (AUClast) of simvastatin metabolite	Up to 10 weeks
Area under plasma concentration-time curve from time 0 to infinity (AUCinf) of simvastatin metabolite	Up to 10 weeks
Maximum observed plasma concentration (Cmax) of simvastatin metabolite	Up to 10 weeks
Time to maximum observed plasma concentration (Tmax) of simvastatin metabolite	Up to 10 weeks
Elimination rate constant (Kel) of simvastatin metabolite	Up to 10 weeks
Terminal half-life (t½), of simvastatin metabolite	Up to 10 weeks
Reporting of treatment emergent adverse events (TEAE) as reported by the study subjects	Up to 10 weeks

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): June 17, 2018
• Primary Completion (Actual): November 24, 2018
• Study Completion (Actual): November 24, 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: Pharmacokinetics; Simvastatin; Pravastatin; Rosuvastatin; Sulfasalazine; Vadadustat; Normal Healthy volunteers; Atrovastatin
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites; Gastrointestinal Agents; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Rosuvastatin Calcium; Pravastatin; Simvastatin; Sulfasalazine
• Other Study ID Numbers: AKB 6548 CI 0030

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