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Effect of Fluconazole on the Pharmacokinetics Properties of Imrecoxib, a Novel NSAID: A Single-center, Open-label, Self-controlled Study in Healthy Chinese Male Volunteers.

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Effect of Fluconazole on the Pharmacokinetics Properties of Imrecoxib, a Novel NSAID: A Single-center, Open-label, Self-controlled Study in Healthy Chinese Male Volunteers.

Clin Ther. 2018 Jul 13;:

Authors: Zuo CZ, Gong Y, Hou XY, Zhang YF, Peng WX, Zhu RH, Zhong DF, Chen XY

Abstract
PURPOSE: Imrecoxib is one type of cyclooxygenase-2 inhibitor with the capability of reducing the potential cardiovascular risk caused by other NSAIDs. Co-administration with other medications can affect the cytochrome P450 (CYP) 2C9 enzyme function; thus, imrecoxib metabolism can be affected. The purpose of this research was to evaluate the effects of fluconazole, which is known to inhibit CYP2C9, on imrecoxib’s pharmacokinetic (PK) parameters.
METHODS: In this single-center, single-arm, open-label, self-controlled study, 12 healthy Chinese male volunteers (mean [SD] age, 22.6 [2.43] years) received the following 2 treatments separated by a washout period of 8days under a fasting state: (1) a single oral dose of imrecoxib 100 mg; and (2) fluconazole 200mg/d over 6days followed by concurrent dosing of imrecoxib 100mg and fluconazole 200mg. Plasma concentrations of imrecoxib (M0) and its metabolites (4′-hydroxymethyl metabolite [M1] and 4′-carboxylic acid metabolite [M2]) for PK analysis were obtained at 0 (baseline) and 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, and 72hours after imrecoxib dosing. Safety and tolerability assessments were performed throughout the study.
FINDINGS: All subjects completed the study. There was 1 adverse event; drug-induced liver damage in 1 subject occurred after he received imrecoxib plus fluconazole, and the subject recovered without any sequelae. Coadministration with fluconazole resulted in much higher plasma imrecoxib concentrations, with an increase of 88% in Cmax and 72% in AUC0-t compared with only imrecoxib treatment, which showed that fluconazole may increase plasma exposure to imrecoxib. Fluconazole also caused a small, but not clinically relevant, decrease in M1 and M2 mean Cmax (13% and 14%, respectively), but there was minimal change in M1 and M2 mean AUC0-t (3% and 2%). However, there were no statistically significant differences in vital signs, clinical laboratory test results, ECGs, or adverse events between treatments.
IMPLICATIONS: Concurrent administration of imrecoxib and fluconazole did not seem to change imrecoxib’s safety profile. The ratio (imrecoxib + fluconazole/imrecoxib) for AUC0-t was 1.72 (90% CI, 1.41-2.11) and for Cmax it was 1.88 (90% CI, 1.59-2.21). Hence, it is necessary to adjust the imrecoxib dose when it is concurrently used with other CYP2C9 inhibitors.

PMID: 30017171 [PubMed – as supplied by publisher]

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