title: Clinical pharmacology of lumiracoxib: a selective cyclo-oxygenase-2 inhibitor.
abstract: Lumiracoxib (Prexige) is a selective cyclo-oxygenase (COX)-2 inhibitor developed for the treatment of osteoarthritis, rheumatoid arthritis and acute pain. Lumiracoxib possesses a carboxylic acid group that makes it weakly acidic (acid dissociation constant [pKa] 4.7), distinguishing it from other selective COX-2 inhibitors. Lumiracoxib has good oral bioavailability (74%). It is rapidly absorbed, reaching maximum plasma concentrations 2 hours after dosing, and is highly plasma protein bound. Lumiracoxib has a short elimination half-life from plasma (mean 4 hours) and demonstrates dose-proportional plasma pharmacokinetics with no accumulation during multiple dosing. In patients with rheumatoid arthritis, peak lumiracoxib synovial fluid concentrations occur 3-4 hours later than in plasma and exceed plasma concentrations from 5 hours after dosing to the end of the 24-hour dosing interval. These data suggest that lumiracoxib may be associated with reduced systemic exposure, while still reaching sites where COX-2 inhibition is required for pain relief. Lumiracoxib is metabolised extensively prior to excretion, with only a small amount excreted unchanged in urine or faeces. Lumiracoxib and its metabolites are excreted via renal and faecal routes in approximately equal amounts. The major metabolic pathways identified involve oxidation of the 5-methyl group of lumiracoxib and/or hydroxylation of its dihaloaromatic ring. Major metabolites of lumiracoxib in plasma are the 5-carboxy, 4'-hydroxy and 4'-hydroxy-5-carboxy derivatives, of which only the 4'-hydroxy derivative is active and COX-2 selective. In vitro, the major oxidative pathways are catalysed primarily by cytochrome P450 (CYP) 2C9 with very minor contribution from CYP1A2 and CYP2C19. However, in patients genotyped as poor CYP2C9 metabolisers, exposure to lumiracoxib (area under the plasma concentration-time curve) is not significantly increased compared with control subjects, indicating no requirement for adjustment of lumiracoxib dose in these subjects. Lumiracoxib is selective for COX-2 compared with COX-1 in the human whole blood assay with a ratio of 515 : 1 in healthy subjects and in patients with osteoarthritis or rheumatoid arthritis. COX-2 selectivity was confirmed by a lack of inhibition of arachidonic acid and collagen-induced platelet aggregation. COX-2 selectivity of lumiracoxib is associated with a reduced incidence of gastroduodenal erosions compared with naproxen and a lack of effect on both small and large bowel permeability. Lumiracoxib does not exhibit any clinically meaningful interactions with a range of commonly used medications including aspirin (acetylsalicylic acid), fluconazole, an ethinylestradiol- and levonorgestrel-containing oral contraceptive, omeprazole, the antacid Maalox, methotrexate and warfarin (although, as in common practice, routine monitoring of coagulation is recommended when lumiracoxib is co-administered with warfarin). As such, dose adjustments are not required when co-administering these agents with lumiracoxib. In addition, moderate hepatic impairment and mild to moderate renal impairment do not appear to influence lumiracoxib exposure.
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. christiane.rordorf@novartis.com
authors.forename: Christiane M
authors.initials: CM
authors.lastname: Rordorf
authors.forename: Les
authors.initials: L
authors.lastname: Choi
authors.forename: Paul
authors.initials: P
authors.lastname: Marshall
authors.forename: James B
authors.initials: JB
authors.lastname: Mangold
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism; D002986:Clinical Trials as Topic; D052246:Cyclooxygenase 2 Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004008:Diclofenac / Q000031:analogs & derivatives; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism; D009930:Organic Chemicals / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010003:Osteoarthritis / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D009930:Organic Chemicals; D004008:Diclofenac; C473384:lumiracoxib