Lumiracoxib: pharmacokinetic and pharmacodynamic profile when coadministered with fluconazole in healthy subjects.
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 B(2) (TxB(2)) 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- infinity ) but had no effect on lumiracoxib mean C(max). The geometric mean ratio (lumiracoxib plus fluconazole/lumiracoxib alone) for AUC(0- infinity ) 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 TxB(2) from predose was not significantly different for lumiracoxib (11.8%) or lumiracoxib plus fluconazole (7.1%); no correlation between lumiracoxib concentration and TxB(2) 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.
Scott
Graham
G
Department of Exploratory Clinical Development, Novartis Pharmaceuticals, Horsham, UK.
Yih
Linda
L
Yeh
Ching-Ming
CM
Milosavljev
Slavica
S
Laurent
Aziz
A
Rordorf
Christiane
C
D000328:Adult; D000935:Antifungal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D004008:Diclofenac / Q000031:analogs & derivatives; D004347:Drug Interactions; D005260:Female; D015725:Fluconazole / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D008565:Membrane Proteins; D009930:Organic Chemicals / Q000097:blood / Q000493:pharmacokinetics*; D011451:Prostaglandin-Endoperoxide Synthases; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors
D000935:Antifungal Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009930:Organic Chemicals; D004008:Diclofenac; D013929:Thromboxane B2; D015725:Fluconazole; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C473384:lumiracoxib