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

J Clin Pharmacol. 2018 Oct;58(10):1305-1313. doi: 10.1002/jcph.1146. Epub 2018 May 10.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antifungal Agents / administration & dosage
  • Antifungal Agents / pharmacokinetics
  • Area Under Curve
  • Cytochrome P-450 CYP2C8
  • Drug Administration Schedule
  • Drug Interactions
  • Female
  • Glucosyltransferases / antagonists & inhibitors*
  • Glycosides / administration & dosage
  • Glycosides / pharmacokinetics*
  • Half-Life
  • Humans
  • Male
  • Rosiglitazone / administration & dosage
  • Rosiglitazone / pharmacokinetics*
  • Triterpenes / administration & dosage
  • Triterpenes / pharmacokinetics*

Substances

  • Antifungal Agents
  • Glycosides
  • MK-3118
  • Triterpenes
  • Rosiglitazone
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • Glucosyltransferases
  • glucan synthase