Disease relevance of Prexige

• Efficacy and safety of four doses of lumiracoxib versus diclofenac in patients with knee or hip primary osteoarthritis: a phase II, four-week, multicenter, randomized, double-blind, placebo-controlled trial [1].
• Anti-hyperalgesic activity of the cox-2 inhibitor lumiracoxib in a model of bone cancer pain in the rat [2].
• Lumiracoxib is effective in the treatment of episodic tension-type headache [3].
• RESULTS: The cumulative incidence of gastroduodenal ulcers >/= 3 mm in diameter was significantly lower in the lumiracoxib groups (200 mg: 4.3%; 400 mg: 4.0%) than in the ibuprofen group (15.7%; p < 0.001) and similar to the celecoxib group (3.2%) [4].
• OBJECTIVE: To determine the efficacy and safety of lumiracoxib for knee osteoarthritis (OA) [5].

High impact information on Prexige

• The search for new COX-2 inhibitors is going on, the development of etoricoxib and lumiracoxib is a step ahead concerning efficacy, tolerability and safety [6].
• 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 [7].
• 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 [7].
• 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 [7].
• Lumiracoxib has a short elimination half-life from plasma (mean 4 hours) and demonstrates dose-proportional plasma pharmacokinetics with no accumulation during multiple dosing [7].

Chemical compound and disease context of Prexige

• METHODS AND PATIENTS: The Therapeutic Arthritis Research and Gastrointestinal Event Trial was a randomized, double-blind, 52-week study of lumiracoxib 400 mg once daily (two to four times the recommended dose for osteoarthritis) versus naproxen 500 mg twice daily or ibuprofen 800 mg three-times daily in patients with osteoarthritis [8].
• The selective COX-II inhibitors (rofecoxib, celecoxib, parecoxib, etoricoxib, valdecoxib, lumiracoxib) show consistently comparable efficacy to that of conventional non-steroidal anti-inflammatory drugs (NSAIDs) in patients with rheumatoid arthritis and osteoarthritis, but have a significantly reduced propensity to cause gastrointestinal toxicity [9].
• In the naproxen substudy, rates of myocardial infarction (clinical and silent) did not differ significantly compared with lumiracoxib in the population not taking low-dose aspirin (hazard ratio 2.37 [95% CI 0.74-7.55], p=0.1454), overall (1.77 [0.82-3.84], p=0.1471), and in patients taking aspirin (1.36 [0.47-3.93], p=0.5658) [10].
• Of 116 094 participants from 114 trial reports including 127 trial populations (40 rofecoxib, 37 celecoxib, 29 valdecoxib + parecoxib, 15 etoricoxib, and 6 lumiracoxib), there were a total of 6394 composite renal events (2670 peripheral edema, 3489 hypertension, 235 renal dysfunction) and 286 arrhythmia events [11].
• However, the reduced incidence of serious GI adverse effects compared to tNSAIDs demonstrated for 2 COX-2 inhibitors (e.g. rofecoxib and lumiracoxib) has been countered by an increased incidence of myocardial infarction and stroke detected in 5 placebo controlled trials involving the COX-2 inhibitors celecoxib, rofecoxib and valdecoxib [12].

Biological context of Prexige

• Pharmacokinetics of lumiracoxib in plasma and synovial fluid [13].
• Lumiracoxib has good oral bioavailability (74%) [7].
• Clinical pharmacology of lumiracoxib: a selective cyclo-oxygenase-2 inhibitor [7].
• The major metabolic pathways identified involve oxidation of the 5-methyl group of lumiracoxib and/or hydroxylation of its dihaloaromatic ring [7].
• Median lumiracoxib protein binding was similar in plasma and synovial fluid (range 97.9-98.3%) [13].

Anatomical context of Prexige

• 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 [13].
• Lumiracoxib was administered orally twice daily from day 10 to day 20 after injection of MRMT-1 tumour cells into one tibia [2].
• In cellular assays, lumiracoxib had an IC(50) of 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition of COX-1 at concentrations up to 30 microM (HEK 293 cells transfected with human COX-1) [14].
• Addition of the selective COX-2 inhibitor lumiracoxib (100 nM) to the superfusion medium did not significantly affect PGE2 or PGD2 release in spinal cord obtained from non-treated mice [15].
• CONCLUSIONS: Lumiracoxib is rapidly and efficiently absorbed throughout the gastrointestinal tract [16].

Associations of Prexige with other chemical compounds

• CONCLUSIONS: Coadministration of lumiracoxib with omeprazole or with an Al/Mg antacid had no clinically significant effect on lumiracoxib single-dose plasma pharmacokinetics [17].
• AIM: To compare the gastroduodenal safety of lumiracoxib with ibuprofen and celecoxib in patients with rheumatoid arthritis [18].
• However, consistent with its low COX-1 inhibitory activity, lumiracoxib at a dose of 100 mg kg(-1) orally caused no ulcers and was significantly less ulcerogenic than diclofenac (P<0.05) [14].
• 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) [19].
• The intrathecal injection of methiothepin (serotonin receptor antagonist) reduced lumiracoxib-induced intrathecal antinociception [20].
• In high risk patients among aspirin users, patients in the ibuprofen substudy had more primary events with ibuprofen than lumiracoxib (2.14% vs 0.25%, p = 0.038), whereas in the naproxen substudy rates were similar for naproxen and lumiracoxib (1.58% vs 1.48%, p = 0.899) [21].

Gene context of Prexige

• 1. This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor [14].
• BACKGROUND AND AIMS: Lumiracoxib is a structurally novel, acidic selective inhibitor of cyclooxygenase (COX)-2 [22].
• In contrast, lumiracoxib did not influence CREB activation and showed no effect on iNOS and COX-2 protein expression [23].
• 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 [19].
• Fever induced in conscious animals by ET-1 (1 pmol icv) or LPS (5 mug/kg iv) was prevented by pretreatments with celecoxib (5 and 10 mg/kg) or lumiracoxib (5 mg/kg) given by oral gavage 1 h before stimuli [24].

Analytical, diagnostic and therapeutic context of Prexige

• Lumiracoxib was generally well tolerated in clinical trials, with a similar overall tolerability profile to those of placebo and other COX-2-selective inhibitors [25].
• 4. Lumiracoxib was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h [14].
• AIM: To compare the gastroduodenal tolerability of lumiracoxib with placebo and naproxen in a randomized, parallel-group, double-blind study [26].
• OBJECTIVE: To evaluate the efficacy of single doses of lumiracoxib, the most selective cyclo-oxygenase (COX)-2 inhibitor, in the treatment of episodic tension-type headache (ETTH), with particular emphasis on time to onset of analgesia [3].
• Females stabilized on Triphasil-28 continued on Triphasil-28 alone for another month (Treatment Period 1), then also received lumiracoxib (400 mg daily) or placebo for 28 days each (Periods 2 and 3) in a double-blind crossover design [27].

References