Lumiracoxib does not affect methotrexate pharmacokinetics in rheumatoid arthritis patients.
BACKGROUND
Methotrexate and nonsteroidal antiinflammatory drugs are frequently coadministered in the treatment of rheumatoid arthritis (RA).


OBJECTIVE
To evaluate the effect of lumiracoxib, a novel cyclooxygenase-2 selective inhibitor, on methotrexate pharmacokinetics and short-term safety in patients with RA.


METHODS
This multicenter, randomized, double-blind, placebo-controlled crossover study enrolled 18 patients (mean age 49.1 y) with stable RA. Patients were randomized to receive methotrexate 7.5-15 mg orally once weekly plus either lumiracoxib 400 mg/day or placebo for 7 days. Patients then received the other treatment combination for an additional 7 days. Serial blood and urine were collected for 24 hours after the methotrexate dose on day 1 (methotrexate alone) and days 8 and 15 (combination treatment).


RESULTS
Plasma methotrexate pharmacokinetics (AUC(0-t), maximum concentration [C(max)], time to C(max)) and methotrexate protein binding were similar for methotrexate alone (108.0 ng.h/mL, 26.7 ng/mL, 1.5 h, and 57.1%, respectively), methotrexate/lumiracoxib (110.2 ng.h/mL, 27.5 ng/mL, 1.0 h, and 53.7%, respectively), and methotrexate/placebo (101.8 ng.h/mL, 22.6 ng/mL, 1.0 h, and 57.0%, respectively). Similarly, no clinically significant difference was found in the urinary excretion of methotrexate. Mean exposure to the 7-OH metabolite was lower when methotrexate was given with lumiracoxib compared with placebo, shown by a reduction in AUC and C(max), although similar amounts of the metabolite were recovered in urine following both lumiracoxib and placebo. Coadministration of methotrexate and lumiracoxib was well tolerated.


CONCLUSIONS
Lumiracoxib had no significant effect on the pharmacokinetics, protein binding, or urinary excretion of coadministered methotrexate in patients with RA.
Hartmann
Stefan N
SN
Exploratory Clinical Development, Novartis Pharma AG, Basel, Switzerland. stefan.hartmann@pharma.novartis.com
Rordorf
Christiane M
CM
Milosavljev
Slavica
S
Branson
Janice M
JM
Chales
Gérard H
GH
Juvin
Robert R
RR
Lafforgue
Pierre
P
Le Parc
Jean Marie
JM
Tavernier
Christian G
CG
Meyer
Olivier C
OC
D000293:Adolescent; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D018592:Cross-Over Studies; D051546:Cyclooxygenase 2; D004008:Diclofenac / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D008565:Membrane Proteins; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D009930:Organic Chemicals / Q000494:pharmacology* / Q000627:therapeutic use; D011451:Prostaglandin-Endoperoxide Synthases
D018501:Antirheumatic Agents; D007527:Isoenzymes; D008565:Membrane Proteins; D009930:Organic Chemicals; D004008:Diclofenac; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C473384:lumiracoxib; C011864:7-hydroxymethotrexate; D008727:Methotrexate