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Lumiracoxib: Pharmacokinetic and Pharmacodynamic Profile When Coadministered with Fluconazole in Healthy Subjects

From the Department of Exploratory Clinical Development, Novartis Pharmaceuticals, Horsham, United Kingdom (Dr. Scott); Departments of Exploratory Clinical Development, Biostatistics, and Bioanalytics, Novartis Pharmaceuticals, East Hanover, New Jersey (L. Yih, Dr. Yeh, S. Milosavljev); PPD Development, Austin, Texas (Dr. Laurent); and Department of Exploratory Clinical Development, Novartis Pharmaceuticals, Basel, Switzerland (Dr. Rordorf).

This two-way crossover study evaluated the effect of fluconazole on the pharmacokinetics and selective COX-2 inhibition of lumiracoxib. Thirteen healthy subjects were randomized to fluconazole (day 1: 400 mg; days 2-4: 200 mg) or no drug. On day 4, all subjects received a single dose of lumiracoxib (400 mg). Lumiracoxib pharmacokinetics were assessed during the following 48 hours. Thromboxane B₂ (TxB₂) inhibition was measured prior to lumiracoxib dosing and 2 hours afterwards. Fluconazole caused a small (18%) but not clinically relevant increase in lumiracoxib mean AUC_0- but had no effect on lumiracoxib mean C_max. The geometric mean ratio (lumiracoxib plus fluconazole/lumiracoxib alone) for AUC_0- was 1.19 (90% confidence interval [CI] = 1.12, 1.27) and for C_max was 1.11 (90% CI = 0.98, 1.27). The decrease in TxB₂ from predose was not significantly different for lumiracoxib (11.8%) or lumiracoxib plus fluconazole (7.1%); no correlation between lumiracoxib concentration and TxB₂ decrease was seen. As fluconazole is a strong inhibitor of cytochrome P450 (CYP) 2C9, other CYP2C9 inhibitors are unlikely to affect lumiracoxib pharmacokinetics with clinical relevance, making dosage adjustment unnecessary.

Key Words: Lumiracoxib • fluconazole • drug interactions • COX-2 inhibitors • pharmacokinetics

Address for reprints: Christiane Rordorf, MD, Department of Exploratory Clinical Development, Novartis Pharma AG, WSJ 210-313, CH-4002, Basel, Switzerland.

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