Oral voriconazole and miconazole oral gel produce comparable effects on the pharmacokinetics and pharmacodynamics of etoricoxib

Eur J Clin Pharmacol (2009) 65:8995 DOI 10.1007/s00228-008-0556-9

PHARMACOKINETICS AND DISPOSITION

Oral voriconazole and miconazole oral gel produce comparable effects on the pharmacokineticsand pharmacodynamics of etoricoxib

Ville V. Hynninen & Klaus T. Olkkola &

Pertti J. Neuvonen & Kari Laine

Received: 20 May 2008 /Accepted: 18 August 2008 / Published online: 9 September 2008 # Springer-Verlag 2008

AbstractPurpose The effect of topical miconazole oral gel and systemic oral voriconazole on the pharmacokinetics of oral etoricoxib was studied in 12 healthy volunteers.

Methods Plasma concentrations of etoricoxib, miconazole, voriconazole, and thromboxane B2 generation were followed after ingestion of 60 mg etoricoxib without pretreatment, after topical administration of miconazole oral gel (85 mg 3, 3 days), or after oral voriconazole (400 mg 2, 1st day, 200 mg 2, 2nd day).

Results Etoricoxib area under the plasma concentration-time curve AUC0 1

and maximum plasma concentration

(Cmax) geometric mean ratios (GMR) with/without miconazole were 1.69 {90% confidence interval (CI); 1.461.92} and 1.12 (90% CI; 0.991.25), respectively, and corresponding GMRs with/without voriconazole were 1.49 (90% CI; 1.371.61) and 1.19 (90% CI; 1.081.31), respectively.

Conclusions Miconazole oral gel and oral voriconazole produced comparable increase in the exposure to etoricoxib, presumably via CYP3A inhibition.

Keywords Etoricoxib . Voriconazole . Miconazole . Pharmacokinetics . CYP3A

Introduction

Etoricoxib is a member of the selective cyclooxygenase (COX)-2-inhibitor family of nonsteroidal anti-inflammatory drugs (NSAIDs) that are widely used to treat pain and inflammation. Oral bioavailability of etoricoxib tablets is nearly 100% [1]. Despite its negligible first-pass metabolism, the elimination of etoricoxib is characterized by extensive metabolism, with less than 1% of an oral dose detected as unchanged drug in urine [2]. In vitro studies indicate that cytochrome P450 3A (CYP3A) is the most important enzyme catalyzing the primary metabolic pathway of etoricoxib (60%), with CYP2C9, CYP2D6, CYP1A2, and CYP2C19 each contributing about 10% [3].

Miconazole is an imidazole antifungal, which was originally developed as a systemic antifungal agent during the 1970s, but due to its low oral bioavailability and high incidence of adverse effects in systemic use, other anti-fungals have replaced miconazole for most of its systemic indications. Nowadays, miconazole is almost solely used as a topical preparation, e.g., as an oral gel for treating oral fungal infections. In vitro, miconazole inhibits many CYPs, namely, CYP3A,...