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

Sponsor

Akebia Therapeutics (Industry)

Overall Status

Completed

CT.gov ID

NCT03801733

Collaborator

(none)

134

Enrollment

Location

Arms

5.3

Actual Duration (Months)

25.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Condition or Disease	Intervention/Treatment	Phase
Drug Interaction Potentiation	Drug: Vadadustat Drug: Simvastatin Drug: Rosuvastatin Drug: Atorvastatin Drug: Pravastatin Drug: Sulfasalazine	Phase 1

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 Design

Study Type:

Interventional

Actual Enrollment :

134 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

This is a three-part sequential design study. Part 2 will be initiated based upon the outcome of Part 1 and Part 3 will be initiated after completion of Part 2.This is a three-part sequential design study. Part 2 will be initiated based upon the outcome of Part 1 and Part 3 will be initiated after completion of Part 2.

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

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

Actual Study Start Date :

Jun 17, 2018

Actual Primary Completion Date :

Nov 24, 2018

Actual Study Completion Date :

Nov 24, 2018

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

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]

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; 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.