Effect of Multiple Doses of Isavuconazole on the Pharmacokinetics of CYP3A4 Substrate Atorvastatin in Healthy Subjects

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

Author address: 

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

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). A recent phase 1 drug interaction study with midazolam confirmed that ISA is a moderate inhibitor of the CYP3A4 enzymea. Atorvastatin, an HMG-CoA reductase inhibitor, is a substrate of CYP3A4 and the organic anion transporter polypeptides, OATP1B1 and 1B3. This study aimed to assess the effect of multiple oral doses of ISA on pharmacokinetics (PK) of atorvastatin and to evaluate the safety and tolerability of the combination. Methods: This was a phase 1, single center, open-label, drug-interaction study. Twenty-four healthy male and female subjects, aged 18-55 years participated in the study. On days 1 and 12, subjects received a single 20 mg oral dose of atorvastatin under fasting conditions. On Days 8 and 9, subjects received 200 mg oral ISA three times daily, administered ~8 h apart. On Days 10 through 15, subjects received 200 mg ISA once daily. PK parameters of atorvastatin were assessed in the presence and absence (Day 12 and Day 1) of ISA. Results: All twenty-four subjects completed the study. No differences in the safety profiles of ISA alone and ISA+atorvastatin groups were observed. Seven subjects had adverse events, all of mild intensity. 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 atorvastatin when given in combination with ISA vs. atorvastatin alone were 137 (129, 145) and 103 (88, 121), respectively. Conclusions:Multiple doses of ISA increased the exposure of atorvastatin by ~1.4-fold. Coadministration of ISA with atorvastatin was safe and well tolerated. aDesai A, et al, EFFECT OF MULTIPLE DOSE OF ISAVUCONAZOLE ON THE PHARMACOKINETICS OF CYP3A4 SUBSTRATE MIDAZOLAM IN HEALTHY VOLUNTEERS.
2013

abstract No: 

NULL

Full conference title: 

53rd Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC, 53rd (2013)