Effect of Multiple Doses of Isavuconazole on the Pharmacokinetics of CYP2D6 Substrate Dextromethorphan in Healthy Subjects

A. Desai, T. Yamazaki, C. Lademacher, D. Kowalski, R. Townsend, Astellas Pharma Global Develop


Purpose: Isavuconazole (ISA), the active moiety of the water soluble prodrug isavuconazonium sulfate, is a novel triazole antifungal agent currently in phase 3 clinical development for the treatment of invasive fungal infections caused by Aspergillus, Candida, or rare mould species. ISA has been found to inhibit CYP2D6 in vitro. Dextromethorphan, an approved probe for in vivo and in vitro CYP2D6 activity, undergoes rapid hepatic conversion to its metabolite dextrorphan. The primary objective of this study was to assess the effect of multiple doses of ISA on the pharmacokinetics (PK) of dextromethorphan and its metabolite dextrorphan after single dose administration.
Methods: This was a phase 1, single-center, open-label, drug-interaction study of twenty-four healthy male and female subjects, aged 18–55 years. On days 1 and 10, subjects received a single dose of 30 mg dextromethorphan. On days 6 and 7, subjects received oral loading doses of 200 mg ISA three times daily, followed by daily 200 mg ISA from days 8 through 12. PK parameters of dextromethorphan and dextrorphan were assessed in the presence/absence (day 10/day 1) of ISA using noncompartmental analysis.
Results: Twenty-three subjects completed the study. One subject, who received one dose of dextromethorphan and oral loading doses of ISA, discontinued the study due a mild adverse event of perioral numbness and numbness in right arm and leg. The geometric mean ratio (%) and 90% confidence intervals (CI) of area under the plasma concentration–time curve from time of dosing extrapolated to infinity (AUCinf) for dextromethorphan and dextrorphan when given in combination with ISA vs. dextromethorphan alone were 118 (102, 135) and 104 (100, 107), respectively. The geometric mean ratio (%) and 90% CI for maximum plasma concentration (Cmax) for dextromethorphan and dextrorphan when given in combination with ISA vs. dextromethorphan alone were 117 (102, 135) and 98 (93, 103) respectively.
Conclusion; Coadministration of ISA and dextromethorphan was well tolerated. Exposure of dextromethorphan increased by ~17% when given in combination with ISA compared with dextromethorphan alone. No changes in the exposure of dextrorphan were observed.

abstract No: 

    • AAPS 2013