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Clin Pharmacol Drug Dev. 2018 Jun 27. doi: 10.1002/cpdd.588. [Epub ahead of print]

Clinical Pharmacokinetics and Drug-Drug Interaction Potential for Coadministered SCY-078, an Oral Fungicidal Glucan Synthase Inhibitor, and Tacrolimus.

Author information

1
SCYNEXIS, Inc., Jersey City, NJ, USA.
2
Riverside Consulting, Wilmington, DE, USA.
3
Worldwide Clinical Trials, Austin, TX, USA.
4
BCH Research Solutions, West Chester, PA, USA.
5
Ready Clinical, LLC, Princeton, NJ, USA.

Abstract

SCY-078 is an orally bioavailable triterpenoid glucan synthase inhibitor in clinical development as an intravenous and oral treatment of fungal infections caused by Candida and Aspergillus species. This was a sequential, single-center, open-label phase 1 study to assess the drug-drug interaction potential between SCY-078 and tacrolimus during concomitant administration in healthy subjects. In cohort 1, period 1, subjects received a single oral dose of tacrolimus 2 mg in the fasted state. In period 2 after a ≥15 day washout, subjects received a single loading dose of SCY-078 1250 mg on day 1 followed by maintenance doses of SCY-780 750 mg on days 2 through 8. On day 3 of period 2, subjects also received a single dose of tacrolimus 2 mg concurrent with SCY-078. In cohort 2, subjects received a loading dose of SCY-078 1250 mg on day 1 followed by maintenance doses of SCY-780 750 mg on days 2 and 3. Pharmacokinetic (PK) parameters were compared to assess both the impact of steady-state SCY-078 on tacrolimus and the impact of tacrolimus on the PK of steady-state SCY-078. The concurrent coadministration of tacrolimus and SCY-078 had no effect on the maximum blood levels of tacrolimus, as evidenced by no change in maximum concentration of drug in blood plasma and a 1.4-fold increase in total area under the plasma drug concentration-time curve. The concurrent coadministration of tacrolimus and SCY-078 resulted in a weaker interaction than typically observed with the azole class of antifungals. The current data indicate that an initial dose adjustment for tacrolimus may not be warranted when combined with SCY-078, as the modest increase in exposure is less than the therapeutic window, although tacrolimus monitoring, as with addition of any new medication, is recommended. These results support the coadministration of SCY-078 and tacrolimus.

KEYWORDS:

antifungal; drug interaction; pharmacokinetics; pharmacology; tacrolimus

PMID:
29947477
DOI:
10.1002/cpdd.588

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