Pharmacokinetics of lumiracoxib in plasma and synovial fluid.
BACKGROUND
Lumiracoxib is a new cyclo-oxygenase-2 (COX-2) selective inhibitor in development for the treatment of rheumatoid arthritis, osteoarthritis and acute pain.


OBJECTIVE
To investigate the pharmacokinetics of lumiracoxib in plasma and knee joint synovial fluid from patients with rheumatoid arthritis.


METHODS
Open-label multiple-dose study evaluating the steady-state pharmacokinetics of lumiracoxib in plasma and synovial fluid after 7 days of treatment with lumiracoxib 400 mg once daily.


METHODS
Males and females aged 18-75 years with rheumatoid arthritis, having moderate to significant synovial fluid effusion of the knee.


METHODS
Following a 7-day washout period for previous nonsteroidal anti-inflammatory drugs, 22 patients (17 female, 5 male) received lumiracoxib 400 mg once daily for seven consecutive days. On day 7, following an overnight fast, a final dose of lumiracoxib was administered and serial blood and synovial fluid samples were collected for up to 28 hours. Lumiracoxib and its metabolites (4'-hydroxy-lumiracoxib and 5-carboxy-4'-hydroxy-lumiracoxib) were measured by validated high performance liquid chromatography-mass spectrometry methods. The steady-state pharmacokinetics of lumiracoxib were evaluated in plasma and synovial fluid by both a population pharmacokinetic model and noncompartmental analysis.


RESULTS
Lumiracoxib was rapidly absorbed (peak plasma concentration at 2 hours) and the terminal elimination half-life in plasma was short (6 hours). Lumiracoxib concentrations were initially higher in plasma than in synovial fluid; however, from 5 hours after administration until the end of the 28-hour assessment period, concentrations of lumiracoxib were higher in synovial fluid than in plasma. Peak drug concentration in synovial fluid occurred 3-4 hours later than the peak plasma concentration. The mean steady-state trough concentration of lumiracoxib in synovial fluid (454 microg/L) was approximately three times higher than the mean value in plasma (155 microg/L), and the area under the concentration-time curve from 12 to 24 hours after administration was 2.6-fold higher for synovial fluid than for plasma. Median lumiracoxib protein binding was similar in plasma and synovial fluid (range 97.9-98.3%). Concentrations of 4'-hydroxy-lumiracoxib, the active COX-2 selective metabolite, remained low in comparison with parent drug in both plasma and synovial fluid. The concentration of lumiracoxib in synovial fluid at 24 hours after administration would be expected to result in substantial inhibition of prostaglandin E(2) formation.


CONCLUSIONS
The kinetics of distribution of lumiracoxib in synovial fluid are likely to extend the therapeutic action of the drug beyond that expected from plasma pharmacokinetics. These data support the use of lumiracoxib in a once-daily regimen for the treatment of rheumatoid arthritis.
Scott
Graham
G
Novartis Pharmaceuticals, Horsham, West Sussex, UK.
Rordorf
Christiane
C
Reynolds
Christine
C
Kalbag
Jyoti
J
Looby
Michael
M
Milosavljev
Slavica
S
Weaver
Margaret
M
Huff
John P
JP
Ruff
Dennis A
DA
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004008:Diclofenac / Q000031:analogs & derivatives; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009930:Organic Chemicals / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013582:Synovial Fluid / Q000378:metabolism; D014018:Tissue Distribution
D016861:Cyclooxygenase Inhibitors; D009930:Organic Chemicals; D004008:Diclofenac; C473384:lumiracoxib