Effect of Multiple Doses of Ketoconazole on the Pharmacokinetics of Isavuconazole in Healthy Subjects

T. Yamazaki, H. Pearlman, D. Kowalski, C. Lademacher, A. Desai, R. Townsend


Background: Isavuconazole (ISA) is a novel broad-spectrum triazole antifungal in development as a water-soluble prodrug in IV and oral formulations for treatment of invasive fungal disease. Isavuconazole is a cytochrome P450 (CYP) 3A4 substrate and moderate CYP3A4 inhibitor. Ketoconazole (KETO) has been widely used as a strong, reversible inhibitor to determine the impact of CYP3A4 inhibition on the clearance of a CYP3A4 substrate in vivo. This study assessed the effect of twice-daily (BID) KETO on the pharmacokinetics (PK) of ISA. Additionally, safety and tolerability of the combination, as well as that of a single dose of ISA were evaluated. KETO 200 mg BID was selected to evaluate the interaction potential with ISA, which has high oral bioavailability (>98%) and a very long half-life (80–120 h).
Methods: This was a Phase 1, open-label, 2-arm study in healthy subjects aged 18–55 years. Subjects were randomized to one of two treatment arms:Arm 1: A single dose of ISA 200 mg on Day 1. Arm 2: KETO 200 mg BID on Days 1–24 and a single dose of ISA 200 mg on Day 4. Primary PK parameters were area under the concentration–time curve (AUC) from the time of dosing extrapolated to time infinity (AUC∞) and maximum drug concentration (Cmax) at Day 1 (Arm 1) or 4 (Arm 2).
Results: All 24 subjects completed the study. Two subjects in Arm 1 and 5 in Arm 2 experienced adverse events, all of mild intensity. The geometric mean ratios (%) of AUC∞ and Cmax for ISA, when given in combination with KETO vs ISA alone were 522 (90% confidence interval [CI]: 409, 666) and 109 (90% CI: 93, 127), respectively. No differences in the safety profiles of ISA alone or ISA and KETO combined were observed.
Conclusions: Multiple doses of KETO increased the exposure to ISA ~5.2-fold. Co-administration of KETO with single dose ISA was safe and well tolerated in this study; single dose ISA was also well tolerated.
ClinicalTrials.gov Identifier: NCT01657838

abstract No: 

    • ICAAC 54th (2014)