Background: Isavuconazole (ISA), the active moiety of the watersoluble 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. Preclinical studies have shown that ISA may inhibit transport via the organic cation transporter 2 (OCT2). Metformin (MET) is a substrate of OCT2. This study assessed the effect of multiple oral doses of ISA on the pharmacokinetics (PK) of MET, and evaluated the safety and tolerability of the combination.
Methods: This was a Phase I, single-center, open-label, druginteraction study. Twenty-four healthy male and female subjects, aged 20–53 years, participated in the study. On Days 1 and 8, subjects received a single oral dose of MET hydrochloride 850 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 given once daily. PK parameters of MET were assessed in the presence and absence (Day 8 and Day 1) of ISA using non-compartmental analysis.
Results: Twenty-one subjects completed the study – 1 subject each discontinued after receiving MET alone and ISA alone due to an adverse event (AE); 1 withdrew for personal reasons. The geometric mean ratios (%) of area under the plasma concentration–time curve from time of dosing extrapolated to infinity and maximum plasma concentration for ISA + MET vs MET alone were 152 (95% confidence interval [CI]: 138, 168) and 123 (95% CI: 109, 140), respectively. The percentage of subjects experiencing an AE was higher after receiving MET (42%) and ISA alone (26%) compared with ISA + MET (19%).
Conclusions: Multiple doses of ISA increased the exposure of MET by 52%. Co-administration of ISA with MET was well tolerated. ClinicalTrials Identifier: NCT01884558
- ASCPT 2014