Drug Interaction Study of Isavuconazole and Warfarin in Healthy Male Subjects

• Composite of PK variables for R-warfarin (in plasma): AUCinf, AUClast, Cmax [ Time Frame: 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 ] [ Designated as safety issue: No ]
• Composite of Pharmacokinetic (PK) variables for S-warfarin and R-warfarin (in plasma): tmax, Vz /F, CL/F, and t1/2 [ Time Frame: 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 ] [ Designated as safety issue: No ]
  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)
• PK variable for isavuconazole (in plasma): trough concentration (Ctrough) [ Time Frame: Days 18-20 and Days 22-27, predose and Day 28 predose and 24 hours post dose ] [ Designated as safety issue: No ]
• Composite of PK variable for isavuconazole (in plasma): AUCtau , Cmax, and tmax [ Time Frame: 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 ] [ Designated as safety issue: No ]
  AUC during the time interval between consecutive dosing (AUCtau)
• Pharmacodynamic Variables: MAXINR, AUCINR, MAXPT, and AUCPT [ Time Frame: Day 1 and Day 20 predose and at 6, 12, 24, 48, 72, 96, 168, and 216 hours post-warfarin-dose ] [ Designated as safety issue: No ]
  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)
• Safety assessed by recording of adverse events, clinical laboratory evaluation, electrocardiograms (ECGs) physical examinations, and vital signs [ Time Frame: Day 1 through Day 29, Day 35 ± 2 ] [ Designated as safety issue: No ]

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.

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.

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

• Drug: Isavuconazole
  oral
  Other Name: BAL8557
• Drug: Warfarin
  oral
  Other Name: Coumadin

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