Drug Interaction Study of Isavuconazole and Warfarin in Healthy Male Subjects

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Pharmacokinetics of Isavuconazole, Pharmacokinetics of S- and R-warfarin, Pharmacodynamics of Warfarin, Healthy Volunteers

Intervention / Treatment
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* Drug: Isavuconazole
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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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

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

Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Isavuconazole and warfarin<br>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<br>* oral<br>* Other names: BAL8557;Drug: Warfarin<br>* oral<br>* Other names: Coumadin;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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isavuconazole, warfarin, Healthy Volunteers, BAL8557, Coumadin