Effect of multiple doses of Isavuconazole on the pharmacokinetics of CYP3A4 substrate cyclosporine in healthy subjects

Yamazaki T., Zadeikis N., Pearlman H., Desai A., Kowalski D. and Townsend R.

Abstract: 

BACKGROUND: Isavuconazonium sulfate is a water soluble prodrug developed for oral and intravenous administration, which is converted in plasma to the active drug Isavuconazole (ISA), a broad-spectrum triazole that inhibits sterol 14 α-demethylase. A recent Phase 1 drug inhibitory study with midazolam, confirmed that ISA is a moderate inhibitor of the CYP3A4 enzyme. Cyclosporine (CYC), a calcineurin-inhibitor immunosuppressant is both a substrate of CYP3A4 and an inhibitor of multiple transporters p-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and organic anion transporter polypeptides (OATP1B1 and 1B3). Interactions with drugs either increase/decrease CYC concentration and may potentiate kidney malfunction. This study aimed to assess the effect of multiple oral doses of ISA on a single 300 mg dose of oral CYC.
Methods: This was a Phase I, single center, open-label, drug interaction study of 24 healthy male and female subjects, aged 18-54 years. On Days 1 and 15, subjects received a single 300 mg oral dose of CYC under fasting conditions. On Days 11 and 12, subjects received oral loading doses of 200 mg ISA three times daily (TID). On Days 13-18, subjects received ISA 200 mg once daily (QD). Pharmacokinetic (PK) parameters of CYC were assessed in the presence/absence (Day 15 to Day 1) of ISA using non-compartmental analysis.
Results: Of the 24 subjects, 19 completed the study. Five subjects discontinued from the study due to mild AEs. Three subjects discontinued after receiving the single dose of CYC, and two discontinued after 4 days of ISA. The geometric mean ratio (%) and 90% confidence intervals (CI) of area under the plasma concentration time curve from time of dosing extrapolated to infinity (AUC∞) and maximum plasma concentration (Cmax) for CYC when given in combination with ISA vs. CYC alone were 128.66 (115.36, 143.50) and 106.27 (95.26, 118.55), respectively.
Conclusion: A slight increase in the AUC (29%) of CYC was observed in the presence of ISA. Co-administration of CYC and ISA was generally well tolerated.

    • ASCPT 2013