Effect of Multiple Doses of Isavuconazole on the Pharmacokinetics of Methotrexate in Healthy Subjects

Takao Yamazaki, Amit Desai, Donna Kowalski, Christopher Lademacher, Helene Pearlman, Diane Rammelsberg, Robert Townsend


Background: Isavuconazole (ISA), the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a novel triazole antifungal agent currently in Phase III clinical development for treatment of invasive fungal infections caused by Aspergillus, Candida, or rare mold species. In preclinical studies, ISA inhibited the efflux transporter, breast cancer resistance protein (BCRP). Methotrexate (MTX) is a substrate of BCRP. This study aimed to assess the effect of multiple oral doses of ISA on the pharmacokinetics (PK) of a single dose of MTX and to evaluate the safety and tolerability of the combination.
Methods: This was a Phase I, single-center, open-label, drug-interaction study. Twenty-four healthy male subjects, aged 20–55 years, participated in the study. On Days 1 and 8, subjects received a single oral dose of MTX sodium 7.5 mg. On Days 4 and 5, subjects received ISA 200 mg 3 times a day, ~8 h apart. On Days 6–9, ISA 200 mg was administered once daily. PK parameters of MTX were assessed in the presence and absence (Day 8 and Day 1) of ISA using non-compartmental analysis.
Results: Twenty-three subjects completed the study; no subjects discontinued due to an adverse event (AE). The geometric mean ratios (%) of area under the plasma concentration–time curve from time of dosing extrapolated to infinity, and maximum plasma concentration for MTX when given in combination with ISA vs MTX alone, were 97 (95% confidence interval [CI]: 90, 105) and 89 (95% CI: 83, 97), respectively. Nine (38%) subjects experienced AEs. The percentage of subjects experiencing an AE was higher after receiving ISA alone (33%) compared with MTX alone (13%) and ISA + MTX (8%).
Conclusions: Multiple doses of ISA did not alter the PK of MTX. Co-administration of ISA with MTX was well tolerated. ClinicalTrials Identifier: NCT01884636

    • ASCPT 2014