Drug Interaction Study of Isavuconazole and Warfarin in Healthy Male Subjects

A Phase 1, Open-Label, Sequential Study of the Effect of Multiple Doses of Isavuconazole on the Pharmacokinetics of a Single Dose of Warfarin in Healthy Male Subjects

The purpose of this study is to assess the effect of multiple doses of isavuconazole on the pharmacokinetics (PK) of warfarin after single dose administration.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers; Pharmacokinetics of Isavuconazole; Pharmacokinetics of S- and R-warfarin; Pharmacodynamics of Warfarin
• Intervention / Treatment: Drug: Isavuconazole; Drug: Warfarin

Detailed Description

Subjects will receive a single dose of warfarin on Day 1 followed by a 15 day wash-out period (time from warfarin dosing to isavuconazole dosing).

On Days 16 and 17, isavuconazole will be dosed three times daily (TID). TID doses will be administered 8 hours apart. On Days 18 through 28, isavuconazole will be administered once daily (QD). All subjects will be administered a single dose of warfarin on Day 20. A follow up visit will occur approximately 7 days after the last dose of isavuconazole. Blood samples for pharmacokinetics will be collected throughout the study.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • West Bend, Wisconsin, United States, 53095
      • Spaulding Clinical

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:

• Subjects must have BMI of 18 to 32 kg/m2 and a body weight of at least 45 kg
• Subjects must have normal laboratory values especially for ALT, AST, protein C and S, and prothrombin time

Exclusion Criteria:

• The subject has a history of unexplained syncope, cardiac arrest, unexplained cardiac arrhythmia or torsade de pointes, structural heart disease, or family history of Long QT syndrome (suggested by sudden death of a close relative at a young age due to possible or probable cardiac causes)
• The subject has a positive result for hepatitis C antibodies or hepatitis B surface antigen at Screening or is known to be positive for human immunodeficiency virus (HIV)
• The subject has a known or suspected allergy to any of the components of the trial products or the azole class of compounds, or a history of multiple and/or severe allergies to drugs or foods (as judged by the investigator), or a history of severe anaphylactic reactions
• The subject is a smoker (any use of tobacco or nicotine containing products) within 6 months prior to Screening
• The subject has had treatment with prescription drugs or complementary and alternative medicines within 14 days prior to Day -1, or over-the-counter medications within 1 week prior to Day -1
• The subject has received an experimental agent within 30 days or 5 half-lives, whichever is longer prior to Day -1
• The subject has a recent history (within the last 2 years) of drug or alcohol abuse, as defined by the investigator, or a positive drug and/or alcohol screen

Study Plan

How is the study designed?

Design Details

• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Isavuconazole and warfarin; Isavuconazole three times daily (TID) for 2 days followed by once daily (QD) dosing for 11 days and warfarin single doses on Days 1 and 20	Drug: Isavuconazole; oral; Other Names: BAL8557; Drug: Warfarin; oral; Other Names: Coumadin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of Pharmacokinetic (PK) variables for S-warfarin (in plasma): AUCinf, AUClast, Cmax	Area under the curve (AUC) from time 0 extrapolated to infinity (AUCinf), AUC from time of dosing to last quantifiable concentration (AUClast ), and maximum concentration (Cmax)	Days 1 and 20, predose and at 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12,16, 24, 48, 72, 96, 120, 144, 168, and 216 hours postdose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of PK variables for R-warfarin (in plasma): AUCinf, AUClast, Cmax		Days 1 and 20, predose and at 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12,16, 24, 48, 72, 96, 120, 144, 168, and 216 hours postdose
Composite of Pharmacokinetic (PK) variables for S-warfarin and R-warfarin (in plasma): tmax, Vz /F, CL/F, and t1/2	Time to attain Cmax (tmax) , apparent volume of distribution (Vz /F), apparent body clearance after oral dosing (CL/F), and apparent terminal elimination half-life (t1/2)	Days 1 and 20, predose and at 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12,16, 24, 48, 72, 96, 120, 144, 168, and 216 hours postdose
PK variable for isavuconazole (in plasma): trough concentration (Ctrough)		Days 18-20 and Days 22-27, predose and Day 28 predose and 24 hours post dose
Composite of PK variable for isavuconazole (in plasma): AUCtau , Cmax, and tmax	AUC during the time interval between consecutive dosing (AUCtau)	Day 19 predose and at 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 16 hours post dose; and Day 20, predose and at 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, and 36 hours postdose
Pharmacodynamic Variables: MAXINR, AUCINR, MAXPT, and AUCPT	International Normalized Ratio (INR), Maximum observed change INR value (MAXINR), Area under the INR time curve from 0 to 216 hours (AUCINR), Maximum observed change in prothrombin time (PT)value (MAXPT), Area under the PT time curve from 0 to 216 hours (AUCPT)	Day 1 and Day 20 predose and at 6, 12, 24, 48, 72, 96, 168, and 216 hours post-warfarin-dose
Safety assessed by recording of adverse events, clinical laboratory evaluation, electrocardiograms (ECGs) physical examinations, and vital signs		Day 1 through Day 29, Day 35 ± 2

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.
• Collaborators: Basilea Pharmaceutica International Ltd

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (ACTUAL): July 1, 2012
• Study Completion (ACTUAL): July 1, 2012

Study Registration Dates

• First Submitted: August 2, 2012
• First Submitted That Met QC Criteria: August 2, 2012
• First Posted (ESTIMATE): August 6, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): August 28, 2012
• Last Update Submitted That Met QC Criteria: August 27, 2012
• Last Verified: August 1, 2012

More Information

Terms related to this study

• Keywords: Healthy Volunteers; warfarin; BAL8557; Coumadin; isavuconazole
• Additional Relevant MeSH Terms: Anti-Infective Agents; Antifungal Agents; Anticoagulants; Warfarin; Isavuconazole
• Other Study ID Numbers: 9766-CL-0033