Isavuconazole does not affect prednisolone pharmacokinetics in healthy subjects following coadministration of multiple dose Isavuconazole

Desai A., Zadeikis N., Howieson C., 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. Prednisone (P), a synthetic glucocorticoid prodrug is commonly used for its antiinflammatory and immunosuppressive actions. Upon administration, P is readily converted to its active metabolite, prednisolone (Pn), which is primarily metabolized by CYP3A4. Interaction with CYP3A4 inhibitors could increase Pn concentrations and lead to fluid and electrolyte disturbances, hypertension, hyperglycemia and possible infections. This study assessed the CYP3A4 inhibitory effect of multiple oral doses of ISA on a single 20 mg dose of oral P.
Methods: This was a Phase I, single center, open-label, drug interaction study of 21 healthy male and female subjects, aged 19-54 years. On Days 1 and 9, subjects received a single 20 mg oral dose of P under fasting conditions. On Days 5 and 6, subjects received oral loading doses of 200 mg ISA three times daily (TID). On Days 7-10, subjects received ISA 200 mg once daily (QD). Pharmacokinetic (PK) parameters of Pn were assessed in the presence/absence (Day 9 to Day 1) of ISA using non-compartmental analysis.
Results: Of the 21 subjects, 20 completed the study. One subject discontinued due to a moderate adverse event on Day 7. 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 Pn when given in combination with ISA vs. Pn alone were 107.63 (102.01, 113.56) and 96.04 (90.04, 102.44), respectively.
Conclusion: Co-administration of ISA and P was well tolerated. ISA does not alter the PK of a single 20 mg dose of Pn, limiting the potential for untoward glucocortocoid side effects.

    • ASCPT 2013