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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Drug Interaction Potentiation

Intervention / Treatment
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* Drug: Vadadustat
* Drug: Simvastatin
* Drug: Rosuvastatin
* Drug: Atorvastatin
* Drug: Pravastatin
* Drug: Sulfasalazine


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; 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.

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 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rosuvastatin, Vadadustat<br>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<br>* Oral dose of 600 mg QD<br>* Other names: AKB 6548;Drug: Rosuvastatin<br>* Oral Rosuvastatin<br>|
| Experimental: Sulfasalazine. Pravastatin, Vadadustat<br>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<br>* Oral dose of 600 mg QD<br>* Other names: AKB 6548;Drug: Pravastatin<br>* Oral Pravastatin<br>Drug: Sulfasalazine<br>* Oral Sulfasalazine<br>|
| Experimental: Atorvastatin, Simvastatin, Vadadustat<br>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<br>* Oral dose of 600 mg QD<br>* Other names: AKB 6548;Drug: Simvastatin<br>* Oral Simvastatin<br>Drug: Atorvastatin<br>* Oral Atorvastatin<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 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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vadadustat, Normal Healthy volunteers, Pharmacokinetics, Rosuvastatin, Sulfasalazine, Pravastatin, Atrovastatin, Simvastatin