SCY-247, a second-generation triterpenoid antifungal, shows low risk for clinically meaningful interactions with CYP3A4 substrates: results from a phase 1 midazolam drug-drug interaction study

ABSTRACT SCY-247, an oral and intravenous second-generation triterpenoid antifungal, is being developed for treatment and prevention of invasive fungal infections caused by Candida, Aspergillus , and Pneumocystis species. In vitro studies indicated that SCY-247 is metabolized by cytochrome P450 (CYP) 3A4 and 3A5 and that SCY-247 has a lowered potential for CYP450-mediated drug-drug interactions compared with azoles. This phase 1 study in 12 healthy adult participants evaluated the effect of supra-therapeutic repeated doses of SCY-247 on the pharmacokinetics of midazolam, a sensitive substrate of CYP3A4. Participants received midazolam 2 mg oral solution once daily on Day 1 and Day 8. A loading dose of oral SCY-247 300 mg twice daily was administered on Day 3, followed by maintenance dosing of oral SCY-247 300 mg once daily on Days 4 to 9 (for a total of 7 days of SCY-247 dosing). When co-administered with midazolam, SCY-247 was well tolerated in healthy participants, and there were no serious or severe treatment-emergent adverse events. Geometric mean ratios (with and without SCY-247) for the maximum plasma concentration ( C max ) and area under the plasma concentration-time curve from 0 to infinity (AUC 0–inf ) were 1.26 and 1.44, respectively, classifying SCY-247 as a weak CYP3A4 inhibitor using regulatory criteria. Therefore, SCY-247 displayed weak inhibition of CYP3A4 at supra-therapeutic doses of 300 mg daily, in contrast to posaconazole and voriconazole, which are strong CYP3A4 inhibitors, and isavuconazole, a moderate CYP3A4 inhibitor. These data are supportive of improved clinical management for CYP3A4 drug-drug interactions with SCY-247 when compared to azoles, particularly relevant in the prophylaxis setting.