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

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

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

Study Overview

• Status: Withdrawn
• Conditions: Pharmacokinetics; Pharmacodynamics
• Intervention / Treatment: Drug: AZD9668; Drug: Warfarin

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Linköping, Sweden
    • Research Site
  • Uppsala, Sweden
    • Research Site

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Wolfgang Kühn, MD, Quintiles AB, Phase 1 Services; Study Director: Christopher D O'Brien, MD, PhD, AstraZeneca R&D; Principal Investigator: Ingemar Bylesjö, MD, Berzelius Clinical Reseach Centre

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Anticipated): December 1, 2010
• Study Completion (Anticipated): December 1, 2010

Study Registration Dates

• First Submitted: September 21, 2010
• First Submitted That Met QC Criteria: October 1, 2010
• First Posted (Estimate): October 4, 2010

Study Record Updates

• Last Update Posted (Estimate): January 29, 2013
• Last Update Submitted That Met QC Criteria: January 28, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: pharmacokinetics; Phase 1; warfarin; pharmacodynamics; Drug-Drug interaction; AZD9668; resulting from AZD9668 and Warfarin interaction
• Additional Relevant MeSH Terms: Anticoagulants; Warfarin
• Other Study ID Numbers: D0520C00013; 2010-022360-12 (EudraCT Number)