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

Desai A., Zadeikis N., Pearlman H., Yamazaki T., 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. Tacrolimus (TAC), a calcineurin-inhibitor immunosuppressant indicated for prophylaxis of organ rejection in patients receiving allogenic liver, kidney or heart transplants has a narrow therapeutic index and is a substrate of CYP3A4. This study aimed to assess the effect of multiple oral doses of ISA on TAC pharmacokinetics (PK) after single oral dose administration.
Methods: This was a Phase I, single center, open-label, drug interaction study of 24 healthy male and female subjects, aged 19-55 years. On Days 1 and 20, subjects received a single 5 mg oral dose of TAC under fasting conditions. On Days 16 and 17, subjects received oral loading doses of 200 mg ISA three times daily, administered approximately 8 hours apart. On Days 18 through 28, subjects received ISA 200 mg once daily. PK parameters of TAC were assessed in the presence/absence of ISA (Day 20/Day1) using non-compartmental analysis.
Results: Of the 24 subjects who initiated this study, 20 completed it. Four subjects discontinued due to mild adverse events; two subjects discontinued after a single dose of TAC on Day 1, one subject discontinued on Day 18 (prior to receiving the combination TAC and ISA) and one subject discontinued on Day 25. 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 TAC when given in combination with ISA vs. TAC alone were 225.09 (90% confidence interval [CI]: 190.73, 265.65) and 141.69 (90% CI: 122.41, 164.01), respectively.
Conclusion: There was a 2.25-fold increase in the AUC of TAC in the presence of ISA. Coadministration of TAC and ISA was well tolerated.

    • ASCPT 2013