Effect of Multiple Doses of Isavuconazole on the Pharmacokinetics of Oral Contraceptive with Ethinyl Estradiol and Norethindrone in Healthy Subjects

Effect of Multiple Doses of Isavuconazole on the Pharmacokinetics of Oral Contraceptive with Ethinyl Estradiol and Norethindrone in Healthy Subjects

Abstract: 

Background: Isavuconazole (ISA), the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a novel triazole antifungal agent currently in Phase III development for treatment of invasive fungal infections. ISA is a moderate inhibitor of the CYP3A4 enzyme. Ethinyl estradiol (EE), the main component of many oral contraceptives (OC), is metabolized by CYP3A4/5 and CYP2C9. This study assessed the effect of multiple oral doses of ISA on the pharmacokinetics (PK) of EE and norethindrone (NE).
Methods: Twenty-four healthy, postmenopausal female subjects participated in this Phase I, open-label, drug-interaction study. On Days 1 and 13, subjects received a single oral dose of OC, containing EE 35 μg/NE 1 mg. On Days 9 and 10, subjects received ISA 200 mg 3 times a day, ~8 h apart. On Days 11–16, ISA 200 mg was given once daily. PK parameters of EE and NE were assessed in the presence and absence (Day 13 and Day 1) of ISA using non-compartmental analysis.
Results: Twenty-three subjects completed the study. One subject experienced an SAE of gastroesophageal reflux disease and gastritis on Day 29, after completing ISA + OC dosing. This subject additionally experienced an adverse event of elevated liver function tests (LFTs). One subject withdrew due to LFTs during OC monotherapy. The geometric mean ratios (GMRs; %) of the area under the plasma concentration–time curve from time of dosing extrapolated to infinity (AUCμ) and maximum plasma concentration (Cmax) for EE during OC + ISA vs OC alone were 108 (95% confidence interval [CI]: 103, 113) and 114 (95% CI: 103, 126), respectively. The GMRs of AUCμ and Cmax for NE during OC + ISA vs OC alone were 116 (95% CI: 109, 123) and 106 (95% CI: 93, 120), respectively.
Conclusions: Co-administration of ISA with OC did not result in a significant PK interaction, and was well tolerated. ClinicalTrials Identifier: NCT01597986

    • ASCPT 2014