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
| Autor: | Christy Corr, David Angulo, Michele Hyman, George Atiee, Gail Murphy, Michael S. Willett, Stephen A. Wring |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine Drug Antifungal Agents media_common.quotation_subject Metabolite 030106 microbiology CYP drug interaction Pharmacology Loading dose Drug Administration Schedule Cytochrome P-450 CYP2C8 Rosiglitazone 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Humans Medicine Drug Interactions antifungal agent Pharmacology (medical) Glycosides 030212 general & internal medicine Dosing CYP2C8 enfumafungin derivative media_common business.industry SCY‐078 Crossover study Triterpenes chemistry Glucosyltransferases Area Under Curve Female business glucan synthase inhibitor Half-Life medicine.drug |
| Zdroj: | Journal of Clinical Pharmacology |
| ISSN: | 0091-2700 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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