Lack of Impact by SCY-078, a First-in-Class Oral Fungicidal Glucan Synthase Inhibitor, on the Pharmacokinetics of Rosiglitazone, a Substrate for CYP450 2C8, Supports the Low Risk for Clinically Relevant Metabolic Drug-Drug Interactions

Abstract

SCY-078, the first in a new class of β 1,3-glucan synthesis inhibitors, is being developed as an oral and intravenous antifungal treatment for Candida and Aspergillus species fungal infections. In vitro, studies indicated SCY-078 is an inhibitor of cytochrome P450 (CYP) 2C8 with markedly lower effect over other CYP isozymes. To examine clinically relevant effects of the potential interaction with SCY-078, this phase 1, open-label, 2-period crossover study evaluated the pharmacokinetic parameters of rosiglitazone, a sensitive substrate of CYP2C8 metabolism, in the absence and presence of SCY-078 dosed to therapeutically relevant SCY-078 concentration exposure after repeat dosing. Healthy adult subjects were randomized to 2 treatment sequences: a single oral 4-mg rosiglitazone dose alone on day 1 or a 1250-mg SCY-078 loading dose on day 1 followed by a once-daily 750-mg SCY-078 dose for an additional 7 days (reflecting the clinical regimen evaluated during phase 2 studies for infections by Candida species) and concurrent administration of a single oral 4-mg rosiglitazone dose on day 3, before alternating following a ≥10-day washout. The exposure to SCY-078 observed in this study was in line with the intended exposure for treatment of invasive fungal infections. The 90% confidence intervals for rosiglitazone exposure geometric mean ratios were within the prespecified no effect interval of 0.70-1.43. Additionally, maximum concentration values for rosiglitazone and its metabolite, N-desmethylrosiglitazone, were not significantly affected by co-administration with SCY-078. Overall, rosiglitazone exposure was not impacted to a clinically meaningful extent with co-administration of therapeutically relevant SCY-078 concentration exposure after repeat dosing. The results are indicative of low risk for interaction of SCY-078 with drugs metabolized via the CYP family of enzymes.

Keywords: CYP drug interaction; SCY-078; antifungal agent; enfumafungin derivative; glucan synthase inhibitor.