Effect of Multiple Doses of Isavuconazole on the Pharmacokinetics of CYP1A2 Substrate Caffeine and CYP2C8 substrate Repaglinide in Healthy Subjects.

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

Abstract: 

Background: Isavuconazole (ISA) is a novel, broad-spectrum, triazole antifungal available as a water-soluble prodrug in IV and oral formulations for treatment of invasive fungal disease. An in vitro CYP450 metabolism study suggests that ISA has the potential to induce CYP1A2 and CYP2C8. Induction of CYP1A2 and CYP2C8 can decrease the systemic exposure of substrates metabolized by these CYPs, thereby decreasing efficacy. The primary objective of this study was to assess the effect of multiple doses of ISA on the pharmacokinetics (PK) of caffeine (CAF; CYP1A2 substrate) and repaglinide (REP; CYP2C8 substrate) after single dose administration.
Methods: This was a Phase 1, single-center, open-label, sequential-dosing, drug-interaction study of 24 healthy male subjects, 18–55 years of age. On Days 1 and 14, subjects received single oral doses of REP 0.5 mg. On Days 3 and 16, subjects received single oral doses of CAF 200 mg. On Days 5 and 6, subjects received oral loading doses of ISA 200 mg three times daily. On Days 7–17, subjects received ISA 200 mg once daily. PK parameters of REP and CAF were assessed in the presence and absence of ISA (REP: Days 14 and 1; CAF: Days 16 and 3) using non-compartmental analysis.
Results: Twenty-two subjects completed the study; 2 subjects discontinued due to adverse events (AEs) during ISA alone. Only 9 of 24 subjects reported AEs during the study and most were mild in intensity. The geometric mean ratios (GMR) of area under the plasma concentration–time curve from time of dosing extrapolated to infinity (AUC∞) and maximum plasma concentration (Cmax) for REP when given in combination with ISA vs REP alone were 92% (90% confidence interval [CI]: 86, 100) and 86% (90% CI: 79, 93), respectively. The GMRs of AUC∞ and Cmax for CAF when given in combination with ISA vs CAF alone were 104% (90% CI: 97, 112) and 99% (90% CI: 93, 107), respectively.
Conclusions: Multiple doses of ISA decreased the exposure of REP by 8% and increased the exposure of CAF by 4%. In this study co-administration of ISA with REP or with CAF was well tolerated.
ClinicalTrials.gov Identifier: NCT02128321

abstract No: 

A-696
    • ICAAC 54th (2014)