Effect of Multiple Doses of Isavuconazole on the Pharmacokinetics of CYP2B6 Substrate Bupropion in Healthy Subjects

Ref ID: 19287

Author:

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

Author address:

Astellas Pharma Global Dev., Inc., Northbrook, IL.

Full conference title:

53rd Interscience Conference on Antimicrobial Agents and Chemotherapy

Date: 10 September 2014

Abstract:

Background: Isavuconazole (ISA), the active moiety of water soluble prodrug isavuconazonium sulfate, is a novel triazole antifungal agent currently in phase 3 clinical development for treatment of invasive fungal infections (caused by Aspergillus, Candida, or rare mould species). An in vitro CYP450 metabolism study suggests that ISA has the potential to induce CYP2B6. Induction of CYP2B6 can decrease systemic exposure to bupropion, which can result in decreased drug exposure and antidepressant efficiency. The primary objective of this study was to assess the effect of multiple doses of isavuconazole on the pharmacokinetics (PK) of bupropion and its metabolite, hydroxybupropion, 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 15, subjects received a single 100 mg oral dose of bupropion under fasting conditions. On Days 8 and 9, subjects received oral loading doses of 200 mg ISA three times daily. On Days 10 through 18, subjects received 200 mg ISA once daily. PK parameters of bupropion and hydroxybupropion were assessed in the presence/absence (Day 15/ Day 1) of ISA using non-compartmental analysis. Results: All twenty-four subjects
completed the study. Five subjects reported adverse
events. No differences in the safety profiles of ISA alone
and ISA+bupropion groups were observed. The geometric
mean ratio (%) and 90% confidence intervals (CI) of area
under the plasma concentration time curve from time of
dosing extrapolated to infinity (AUC8734;) and maximum
plasma concentration (Cmax) for bupropion when given in
combination with ISA vs. bupropion alone were 58 (52, 64)
and 69 (62, 77), respectively. The geometric mean ratio
(%) and 90% CI of AUC8734; and Cmax for hydroxybupropion
when bupropion was given in combination with ISA vs.
bupropion alone were 187 (168, 207) and 263 (246, 281),
respectively.Conclusions: Multiple doses of ISA decreased
the exposure of bupropion by 42%, with a concurrent
187% increase in the exposure of hydroxybupropion. Coadministration of ISA with bupropion was generally safe and well tolerated.

Abstract Number: NULL

Conference Year: 2013

Link to conference website: NULL

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