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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
Author(s) -
Wring Stephen,
Murphy Gail,
Atiee George,
Corr Christy,
Hyman Michele,
Willett Michael,
Angulo David
Publication year - 2018
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1146
Subject(s) - rosiglitazone , medicine , pharmacokinetics , pharmacology , endocrinology , chemistry , receptor
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 th e 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.