Effect of multiple doses of Isavuconazole on the pharmacokinetics of sirolimus in healthy subjects

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


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 broadspectrum triazole that inhibits sterol 14 α-demethylase. A recent Phase 1 drug inhibitory study with the CYP3A4 probe, midazolam, confirmed that ISA is a moderate inhibitor of the CYP3A4 enzyme. Further, in vitro studies indicate that ISA inhibits p-glycoprotein (P-gp). Sirolimus (SIR), a known substrate for both CYP3A4 and P-gp, is an immunosuppressive agent indicated for the prophylaxis of organ rejection in patients receiving renal transplants. This study aimed to assess the inhibitory effect of multiple oral dose ISA on the pharmacokinetics of a single 2 mg oral dose of SIR.
Methods: This was a Phase I, single center, open-label, drug interaction study of 22 healthy male and female subjects, aged 22 to 53 years. On Days 1 and 26, subjects received a single 2 mg oral dose of SIR under fasting conditions. On Days 22 and 23, subjects received oral loading doses of 200 mg ISA three times daily, administered approximately 8 hours apart. On Days 24 through 34, subjects received 200 mg ISA once daily. Pharmacokinetic (PK) parameters of SIR were assessed in the presence/absence of ISA (Day 26 to Day 1) using noncompartmental analysis.
Results: Of the 22 subjects enrolled, 21 subjects completed the study. One subject was discontinued after receiving a single dose of SIR but prior to receiving ISA due to a pre-existing condition of hyperlipidemia. The geometric mean ratio (%) of area under the plasma concentration-time curve from time of dosing extrapolated to infinity (AUC∞) and maximum plasma concentration (Cmax) for SIR when given in combination with ISA vs. SIR alone were 184.12 (90% confidence interval [CI]: 158.86, 213.40) and 164.50 (90% CI: 141.25, 191.57), respectively.
Conclusion: An approximate 2-fold increase in the exposure of SIR in the presence of ISA was observed. Coadministration of ISA and SIR was well tolerated.

    • ASCPT 2013