A Drug-Drug Interaction Study Between AZD9668 and Warfarin to Study the Effect of AZD9668 on the Metabolism and Effect of Warfarin

Study Overview
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Brief Summary
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The primary purpose of this study is to determine whether the treatment with AZD9668 will affect the metabolism and effect of Warfarin.

Official Title
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A Phase I, Open Label, Fixed Sequence, Single Centre Study in Healthy Volunteers to Investigate the Effects of Repeated Oral Doses AZD9668 on the Pharmacokinetics and Pharmacodynamics of a Single Dose of Warfarin

Conditions
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Pharmacokinetics, Pharmacodynamics

Intervention / Treatment
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* Drug: AZD9668
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed informed consent (including genotyping screening sample for CYP2C9 and VKORC1) prior to any study specific procedures Subjects must be willing to use a barrier method of contraception, unless their partners are post-menopausal or surgically sterile, or if a female partner is of childbearing potential the subject must use a barrier method of contraception (condom) and the partner must use accepted contraceptive methods (oral contraceptive, implant, long term injectable contraceptive or intrauterine device), from first dose of IP (warfarin and AZD9668) until 3 months after last dose of IP (warfarin and AZD9668) Have a body mass index between 19 and 30 kg/m2 (inclusive) and a weight between 50 and 100 kg (inclusive) Be a non-smoker or ex-smoker who has stopped smoking for >6 months prior to Visit 1. Exclusion Criteria: Any clinically significant disease or disorder Subject predicted to have high sensitivity to warfarin based on CYP2C9 and VKORC1 genotypes Any clinically relevant abnormal findings in physical examination

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>AZD9668 - 2 x30mg tablets | Drug: AZD9668<br>* 60 mg orally twice daily for 11 days<br>|
| Experimental: Treatment B<br>Warfarin - 10 x2.5 mg tablets | Drug: Warfarin<br>* 10 x 2.5 (25) mg orally once daily on day 1 and on day 14<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 1 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 2 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 3 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 4 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 5 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 6 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 7 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 8 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 9 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 10 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 11 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 12 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 13 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 14 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 15 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 16 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 17 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 18 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 19 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 20 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 21 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 22 | 
| Pharmacokinetics for (R)- and (S)- Warfarin, measured by maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) |  | Pharmacokinetic (PK) sampling will be performed day 23 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 1 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 2 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 3 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 4 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 5 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 6 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 7 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 8 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 9 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 10 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 11 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 12 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 13 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 14 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 15 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 16 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 17 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 18 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 19 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 20 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 21 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 22 | 
| Pharmacodynamics measured by maximum international normalised ratio ( INRmax) |  | International normalised ratio (INR) sampling will be performed day 23 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics for AZD9668 measured by Css,max |  | Range from day 9 to 23 | 
| Pharmacokinetics for AZD9668 measured by tss,max |  | Range from day 9 to 23 | 
| Pharmacokinetics for AZD9668 measured by Css,min |  | Range from day 9 to 23 | 
| Pharmacokinetics for AZD9668 measured by CLss/F |  | Range from day 9 to 23 | 
| Severity of Adverse Events as a Measure of Safety and Tolerability |  | Adverse events will be collected pre-dose, during treatment and at follow up | 
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability |  | Adverse events will be collected pre-dose, during treatment and at follow up | 
| Pharmacokinetics for (R)- and (S)- Warfarin measured tmax. |  | Range from day 1 to 23 | 
| Pharmacokinetics for (R)- and (S)- Warfarin measured t½. |  | Range from day 1 to 23 | 
| Pharmacokinetics for (R)- and (S)- Warfarin measured CL/F. |  | Range from day 1 to 23 | 
| Pharmacokinetics for (R)- and (S)- Warfarin measured Vz/F. |  | Range from day 1 to 23 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1, Drug-Drug interaction, warfarin, AZD9668, resulting from AZD9668 and Warfarin interaction, pharmacokinetics, pharmacodynamics