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Christiane Rordorf - One of the best experts on this subject based on the ideXlab platform.
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Lack of Effect of Omeprazole or of an Aluminium Hydroxide/Magnesium Hydroxide Antacid on the Pharmacokinetics of Lumiracoxib
Clinical Pharmacokinectics, 2012Co-Authors: Graham Scott, Christine Reynolds, Slavica Milosavljev, Wayne K. Langholff, Magdy Shenouda, Christiane RordorfAbstract:Objective: To evaluate the effects of multiple doses of omeprazole and of a single dose of an aluminium hydroxide/magnesium hydroxide (Al/Mg) antacid on the single-dose plasma pharmacokinetics of Lumiracoxib.
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Lumiracoxib does not affect the ex vivo antiplatelet aggregation activity of low dose aspirin in healthy subjects
The Journal of Clinical Pharmacology, 2005Co-Authors: J. Jermany, Janice Branson, Robert Schmouder, Michel Guillaume, Christiane RordorfAbstract:This randomized, double-blind, placebo-controlled study evaluated the pharmacodynamic effects of concomitant low-dose aspirin and Lumiracoxib in healthy subjects. Participants received Lumiracoxib 400 mg once daily (n = 14) or placebo (n = 14) for 11 days, with concomitant low-dose aspirin (75 mg once daily) from days 5 to 11. Ex vivo pharmacodynamic assessments included assays of platelet aggregation and urinary thromboxane and prostacyclin metabolite profile. Arachidonic acid-stimulated platelet aggregation was reduced from 76.3% on clay 4 to 4.8% on day 11 in the placebo group and from 75.8% on day 4 to 5.1% on day 11 in the Lumiracoxib group. Collagen-induced platelet aggregation was reduced from 77.5% on day 4 to 52.8% on day 11 in the placebo group and from 79.5% on day 4 to 55.9% on day 11 in the Lumiracoxib group. Urinary thromboxane and prostacyclin were unaffected by Lumiracoxib. In conclusion, concomitant Lumiracoxib did not interfere with the cyclooxygenase-1-mediated antiplatelet effects of low-dose aspirin.
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Clinical pharmacology of Lumiracoxib: a selective cyclo-oxygenase-2 inhibitor.
Clinical pharmacokinetics, 2005Co-Authors: Christiane Rordorf, Les Choi, Paul J. Marshall, James B. MangoldAbstract: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.
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Lumiracoxib Does Not Affect the Ex Vivo Antiplatelet Aggregation Activity of Low‐Dose Aspirin in Healthy Subjects
Journal of clinical pharmacology, 2005Co-Authors: J. Jermany, Janice Branson, Robert Schmouder, Michel Guillaume, Christiane RordorfAbstract:This randomized, double-blind, placebo-controlled study evaluated the pharmacodynamic effects of concomitant low-dose aspirin and Lumiracoxib in healthy subjects. Participants received Lumiracoxib 400 mg once daily (n = 14) or placebo (n = 14) for 11 days, with concomitant low-dose aspirin (75 mg once daily) from days 5 to 11. Ex vivo pharmacodynamic assessments included assays of platelet aggregation and urinary thromboxane and prostacyclin metabolite profile. Arachidonic acid-stimulated platelet aggregation was reduced from 76.3% on clay 4 to 4.8% on day 11 in the placebo group and from 75.8% on day 4 to 5.1% on day 11 in the Lumiracoxib group. Collagen-induced platelet aggregation was reduced from 77.5% on day 4 to 52.8% on day 11 in the placebo group and from 79.5% on day 4 to 55.9% on day 11 in the Lumiracoxib group. Urinary thromboxane and prostacyclin were unaffected by Lumiracoxib. In conclusion, concomitant Lumiracoxib did not interfere with the cyclooxygenase-1-mediated antiplatelet effects of low-dose aspirin.
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Pharmacokinetics of Lumiracoxib in Plasma and Synovial Fluid
Clinical Pharmacokinetics, 2004Co-Authors: Graham Scott, Christiane Rordorf, Christine Reynolds, Jyoti Kalbag, Michael Looby, Slavica Milosavljev, Margaret Weaver, John P. Huff, Dennis A. RuffAbstract:Background umiracoxib 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. Design Open-label multiple-dose study evaluating the steady-state pharmacokinetics of Lumiracoxib in plasma and synovial fluid after 7 days of treatment with Lumiracoxib 400mg once daily. Patient population Males and females aged 18–75 years with rheumatoid arthritis, having moderate to significant synovial fluid effusion of the knee. Outcome measures Following a 7-day washout period for previous nonsteroidal anti-inflammatory drugs, 22 patients (17 female, 5 male) received Lumiracoxib 400mg 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 μg/L) was approximately three times higher than the mean value in plasma (155 μg/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. Conclusion 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.
Xavier Gitton - One of the best experts on this subject based on the ideXlab platform.
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a comparison of the blood pressure changes of Lumiracoxib with those of ibuprofen and naproxen
Journal of Clinical Hypertension, 2008Co-Authors: Michael E Farkouh, Gerhard Krammer, Xavier Gitton, Raban Jeger, Freek W A Verheugt, Howard S Kirshner, Sean Ruland, Kirstin Stricker, Peter Sallstig, Bernhard MelleinAbstract:The 52-week Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) investigated the gastrointestinal and cardiovascular safety profile of Lumiracoxib 400 mg once daily compared with 2 traditional nonsteroidal anti-inflammatory drugs (NSAIDs): ibuprofen 800 mg 3 times daily and naproxen 500 mg twice daily. Data from TARGET were analyzed to examine the effect of Lumiracoxib compared with ibuprofen and naproxen on blood pressure (BP), incidence of de novo and aggravated hypertension, prespecified edema events, and congestive heart failure. Lumiracoxib resulted in smaller changes in BP as early as week 4. Least-squares mean change from baseline at week 4 for systolic BP was +0.57 mm Hg with Lumiracoxib compared with +3.14 mm Hg with ibuprofen (P<.0001) and +0.43 with Lumiracoxib compared with +1.80 mm Hg with naproxen (P<.0001). In conclusion, the use of Lumiracoxib and traditional NSAIDs results in differing BP changes; these might be of clinical relevance.
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A comparison of the blood pressure changes of Lumiracoxib with those of ibuprofen and naproxen.
Journal of clinical hypertension (Greenwich Conn.), 2008Co-Authors: Michael E Farkouh, Gerhard Krammer, Xavier Gitton, Raban Jeger, Freek W A Verheugt, Howard S Kirshner, Sean Ruland, Kirstin Stricker, Peter Sallstig, Bernhard MelleinAbstract:The 52-week Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) investigated the gastrointestinal and cardiovascular safety profile of Lumiracoxib 400 mg once daily compared with 2 traditional nonsteroidal anti-inflammatory drugs (NSAIDs): ibuprofen 800 mg 3 times daily and naproxen 500 mg twice daily. Data from TARGET were analyzed to examine the effect of Lumiracoxib compared with ibuprofen and naproxen on blood pressure (BP), incidence of de novo and aggravated hypertension, prespecified edema events, and congestive heart failure. Lumiracoxib resulted in smaller changes in BP as early as week 4. Least-squares mean change from baseline at week 4 for systolic BP was +0.57 mm Hg with Lumiracoxib compared with +3.14 mm Hg with ibuprofen (P
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Effect of risk factors on complicated and uncomplicated ulcers in the TARGET Lumiracoxib outcomes study
Gastroenterology, 2007Co-Authors: C J Hawkey, Gerhard Krammer, Xavier Gitton, Bernhard Mellein, Kirstin Stricker, Peter Sallstig, D. Richard, Wilfred M. Weinstein, Walter E. Smalley, Patrice MatchabaAbstract:Background & Aims: Selective cyclooxygenase-2 inhibitors were developed to reduce the gastrointestinal risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs). The Therapeutic Arthritis Research and Gastrointestinal Event Trial was the largest study to evaluate primarily the gastrointestinal safety outcomes of selective cyclooxygenase-2 inhibitors. Data from the Therapeutic Arthritis Research and Gastrointestinal Event Trial were used to identify risk factors and investigate the safety of Lumiracoxib in subgroups. Methods: Patients with osteoarthritis (age, ≥50 y) were randomized to receive Lumiracoxib 400 mg once daily, naproxen 500 mg twice daily, or ibuprofen 800 mg 3 times daily for 12 months. Events were categorized by a blinded adjudication committee. The primary end point was all definite or probable ulcer complications. Results: For patients taking NSAIDs, factors associated with an increased risk of ulcer complications were age 65 years or older (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.48–3.59), previous history of gastrointestinal bleed or ulcer (HR, 3.61; 95% CI, 1.86–7.00), non-Caucasian racial origin (HR, 2.10; 95% CI, 1.35–3.27), and male sex (HR, 1.70; 95% CI, 1.08–2.68). With Lumiracoxib, significant risk factors were age 65 years or older (HR, 3.18; 95% CI, 1.40–7.20), male sex (HR, 2.60; 95% CI, 1.25–5.40), non-Caucasian racial origin (HR, 2.16; 95% CI, 1.02–4.59), and concomitant aspirin use (HR, 2.89; 95% CI, 1.40–5.97). Increased risks in patients age 65 years and older were increased further if other risk factors were present. Lumiracoxib maintained an advantage over NSAIDs across all subgroups except aspirin use. Conclusions: Lumiracoxib was associated with a reduced risk of ulcer complications compared with NSAIDs in all significant subgroups except aspirin users.
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Evaluation of the Patient Acceptable Symptom State in a pooled analysis of two multicentre, randomised, double-blind, placebo-controlled studies evaluating Lumiracoxib and celecoxib in patients with osteoarthritis
Arthritis research & therapy, 2007Co-Authors: Maxime Dougados, Alan Moore, Xavier GittonAbstract:Patient Acceptable Symptom State (PASS) is an absolute threshold proposed for symptomatic variables in osteoarthritis (OA) to determine the point beyond which patients consider themselves well and, as such, are satisfied with treatment. Two large previously reported studies of knee OA have shown that both Lumiracoxib and celecoxib were superior to placebo in terms of conventional outcome measures. To assess the clinical relevance of these results from the patient's perspective, the same data pooled from these two studies were analysed with respect to the PASS. In total, 3,235 patients were included in two multicentre, randomised, double-blind studies of identical design. Patients were randomly assigned to receive Lumiracoxib 100 mg once daily (n = 811), Lumiracoxib 100 mg once daily with an initial dose of Lumiracoxib 200 mg once daily for the first 2 weeks (100 mg once daily with initial dose [n = 805]), celecoxib 200 mg once daily (n = 813), or placebo (n = 806) for 13 weeks. Treatments were compared with respect to the PASS criteria (for OA pain, patient's global assessment of disease activity, and the Western Ontario and McMaster Universities Osteoarthritis Index Likert version 3.1 [WOMAC™ LK 3.1] Function [difficulty in performing daily activities] subscale score). At week 13, 43.3%, 45.3%, and 42.2% of patients in the Lumiracoxib 100 mg once daily, Lumiracoxib 100 mg once daily with initial dose, and the celecoxib 200 mg once daily groups, respectively, considered their current states as satisfactory versus 35.5% in the placebo group. Similar results were observed for patient's global assessment of disease activity and WOMAC™ LK 3.1 Function subscale score. This post hoc analysis suggests that the statistical significance of the results observed with Lumiracoxib or celecoxib compared with placebo using conventional outcome variables is complemented by clinical relevance to the patient. Trial registration numbers: NCT00366938 and NCT00367315.
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Gastrointestinal tolerability of Lumiracoxib in patients with osteoarthritis and rheumatoid arthritis.
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 2006Co-Authors: C J Hawkey, Xavier Gitton, Godehard Hoexter, D. Richard, Wilfred M. WeinsteinAbstract:Background & Aims: The aim of this study was to evaluate the gastrointestinal safety of Lumiracoxib, a novel selective cyclooxygenase-2 inhibitor. Methods: Results from 15 Phase II and III randomized studies of Lumiracoxib in osteoarthritis and rheumatoid arthritis were pooled. Patients received Lumiracoxib (200/400 mg/day), celecoxib (200/400 mg/day), rofecoxib (25 mg once daily), diclofenac (75 mg twice daily), ibuprofen (800 mg 3 times daily), naproxen (500 mg twice daily), or placebo. Outcome measures included the incidence of definite or probable ulcer complications (perforations, obstructions, or bleedings as confirmed by an adjudication committee) and symptomatic upper gastrointestinal ulcers, the incidence of prespecified gastrointestinal adverse events, and the discontinuation rate caused by adverse events. All suspected ulcer complications in these 15 studies were adjudicated prospectively. Data from 2 endoscopic studies were pooled separately to assess the cumulative incidence of gastroduodenal ulcers ≥3 mm in diameter. Results: Symptomatic upper gastrointestinal ulcers and ulcer complications were reduced nearly 10-fold with Lumiracoxib (1.7 events per 100 patient-years [95% confidence interval, 1.09–2.39]) compared with nonselective nonsteroidal anti-inflammatory drugs (13.7 events per 100 patient-years [95% confidence interval, 9.47–18.82]). Symptomatic ulcer frequency was markedly lower with Lumiracoxib (0.4%) than with nonselective nonsteroidal anti-inflammatory drugs (2.5%). Discontinuation rates due to gastrointestinal adverse events were higher for nonselective nonsteroidal anti-inflammatory drugs (8.4%) than for Lumiracoxib (3.3%). In the endoscopy analysis, the cumulative frequency of ulcers ≥3 mm in diameter was reduced by >70% for Lumiracoxib versus ibuprofen. Conclusions: Lumiracoxib exhibited a gastrointestinal safety profile superior to nonselective nonsteroidal anti-inflammatory drugs.
C J Hawkey - One of the best experts on this subject based on the ideXlab platform.
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Less small-bowel injury with Lumiracoxib compared with naproxen plus omeprazole
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 2008Co-Authors: C J Hawkey, Christian Ell, Bernd Simon, Jörg G. Albert, Martin Keuchel, Mark E. Mcalindon, Paul Fortun, Stefan Schumann, Wolfgang Bolten, Anthony ShondeAbstract:Background & Aims: The selective cyclooxygenase-2 inhibitor Lumiracoxib has been shown to reduce endoscopically detected ulcers and ulcer complications in the upper gastrointestinal tract compared with nonselective nonsteroidal anti-inflammatory drugs. We investigated whether Lumiracoxib would reduce small-bowel injury compared with naproxen plus omeprazole. Methods: Healthy volunteers were randomized to receive Lumiracoxib 100 mg once daily, naproxen 500 mg twice daily plus omeprazole 20 mg once daily, or placebo in a 16-day double-blind, parallel-group study. Small-bowel mucosal injury and inflammation were assessed by video capsule endoscopy, the lactulose:L-rhamnose permeability assessment, and the fecal calprotectin test. Results: Of 152 randomized subjects, 139 completed the study with valid video capsule endoscopies (Lumiracoxib, n=47; naproxen plus omeprazole, n=45; placebo, n=47). Compared with placebo, an increased number of subjects on naproxen plus omeprazole had small-bowel mucosal breaks (77.8% vs 40.4%, P
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Clinical trial: comparison of the gastrointestinal safety of Lumiracoxib with traditional nonselective nonsteroidal anti-inflammatory drugs early after the initiation of treatment--findings from the Therapeutic Arthritis Research and Gastrointestinal
Alimentary pharmacology & therapeutics, 2008Co-Authors: C J Hawkey, Gerhard Krammer, Kirstin Stricker, D. Richard, Wilfred M. Weinstein, Valda Murphy, Rosemary RebuliAbstract:Summary Background The large (n = 18 325) Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) study demonstrated a significant gastrointestinal benefit with Lumiracoxib 400 mg o.d. (4× the recommended dose in osteoarthritis) vs. naproxen 500 mg b.d. or ibuprofen 800 mg t.d.s. Aim To investigate how early a reduction in ulcer complications could be detected with Lumiracoxib vs. nonselective nonsteroidal anti-inflammatory drugs in TARGET. Methods Pointwise 95% confidence intervals were generated for the between-treatment differences in Kaplan–Meier estimates for definite or probable upper gastrointestinal ulcer complications (ulcer complications) and for all ulcers. Results In patients not on aspirin, there was a significant reduction in all ulcers by day 8 and in ulcer complications by day 16 with Lumiracoxib compared with both nonselective nonsteroidal anti-inflammatory drugs combined, by day 6 (all ulcers) and day 14 (ulcer complications) vs. naproxen and by day 32 (all ulcers) and day 33 (ulcer complications) vs. ibuprofen. Conclusion Even with short-term use, there are gastrointestinal safety benefits for Lumiracoxib vs. nonselective nonsteroidal anti-inflammatory drugs.
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Effect of risk factors on complicated and uncomplicated ulcers in the TARGET Lumiracoxib outcomes study
Gastroenterology, 2007Co-Authors: C J Hawkey, Gerhard Krammer, Xavier Gitton, Bernhard Mellein, Kirstin Stricker, Peter Sallstig, D. Richard, Wilfred M. Weinstein, Walter E. Smalley, Patrice MatchabaAbstract:Background & Aims: Selective cyclooxygenase-2 inhibitors were developed to reduce the gastrointestinal risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs). The Therapeutic Arthritis Research and Gastrointestinal Event Trial was the largest study to evaluate primarily the gastrointestinal safety outcomes of selective cyclooxygenase-2 inhibitors. Data from the Therapeutic Arthritis Research and Gastrointestinal Event Trial were used to identify risk factors and investigate the safety of Lumiracoxib in subgroups. Methods: Patients with osteoarthritis (age, ≥50 y) were randomized to receive Lumiracoxib 400 mg once daily, naproxen 500 mg twice daily, or ibuprofen 800 mg 3 times daily for 12 months. Events were categorized by a blinded adjudication committee. The primary end point was all definite or probable ulcer complications. Results: For patients taking NSAIDs, factors associated with an increased risk of ulcer complications were age 65 years or older (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.48–3.59), previous history of gastrointestinal bleed or ulcer (HR, 3.61; 95% CI, 1.86–7.00), non-Caucasian racial origin (HR, 2.10; 95% CI, 1.35–3.27), and male sex (HR, 1.70; 95% CI, 1.08–2.68). With Lumiracoxib, significant risk factors were age 65 years or older (HR, 3.18; 95% CI, 1.40–7.20), male sex (HR, 2.60; 95% CI, 1.25–5.40), non-Caucasian racial origin (HR, 2.16; 95% CI, 1.02–4.59), and concomitant aspirin use (HR, 2.89; 95% CI, 1.40–5.97). Increased risks in patients age 65 years and older were increased further if other risk factors were present. Lumiracoxib maintained an advantage over NSAIDs across all subgroups except aspirin use. Conclusions: Lumiracoxib was associated with a reduced risk of ulcer complications compared with NSAIDs in all significant subgroups except aspirin users.
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Gastrointestinal tolerability of Lumiracoxib in patients with osteoarthritis and rheumatoid arthritis.
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 2006Co-Authors: C J Hawkey, Xavier Gitton, Godehard Hoexter, D. Richard, Wilfred M. WeinsteinAbstract:Background & Aims: The aim of this study was to evaluate the gastrointestinal safety of Lumiracoxib, a novel selective cyclooxygenase-2 inhibitor. Methods: Results from 15 Phase II and III randomized studies of Lumiracoxib in osteoarthritis and rheumatoid arthritis were pooled. Patients received Lumiracoxib (200/400 mg/day), celecoxib (200/400 mg/day), rofecoxib (25 mg once daily), diclofenac (75 mg twice daily), ibuprofen (800 mg 3 times daily), naproxen (500 mg twice daily), or placebo. Outcome measures included the incidence of definite or probable ulcer complications (perforations, obstructions, or bleedings as confirmed by an adjudication committee) and symptomatic upper gastrointestinal ulcers, the incidence of prespecified gastrointestinal adverse events, and the discontinuation rate caused by adverse events. All suspected ulcer complications in these 15 studies were adjudicated prospectively. Data from 2 endoscopic studies were pooled separately to assess the cumulative incidence of gastroduodenal ulcers ≥3 mm in diameter. Results: Symptomatic upper gastrointestinal ulcers and ulcer complications were reduced nearly 10-fold with Lumiracoxib (1.7 events per 100 patient-years [95% confidence interval, 1.09–2.39]) compared with nonselective nonsteroidal anti-inflammatory drugs (13.7 events per 100 patient-years [95% confidence interval, 9.47–18.82]). Symptomatic ulcer frequency was markedly lower with Lumiracoxib (0.4%) than with nonselective nonsteroidal anti-inflammatory drugs (2.5%). Discontinuation rates due to gastrointestinal adverse events were higher for nonselective nonsteroidal anti-inflammatory drugs (8.4%) than for Lumiracoxib (3.3%). In the endoscopy analysis, the cumulative frequency of ulcers ≥3 mm in diameter was reduced by >70% for Lumiracoxib versus ibuprofen. Conclusions: Lumiracoxib exhibited a gastrointestinal safety profile superior to nonselective nonsteroidal anti-inflammatory drugs.
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Therapeutic arthritis research and gastrointestinal event trial of Lumiracoxib - study design and patient demographics.
Alimentary pharmacology & therapeutics, 2004Co-Authors: C J Hawkey, Xavier Gitton, Michael E Farkouh, Elena Ehrsam, J. Huels, Paul G. RichardsonAbstract:Summary Background : Cyclooxygenase-2 selective inhibitors were developed in order to reduce the incidence of life-threatening gastrointestinal ulcer complications compared with non-selective non-steroidal anti-inflammatory drugs. Previous outcomes studies have, variously, lacked power to investigate this endpoint, focused on broader outcomes, or been too small to quantify the influence of aspirin. Aim : To evaluate Lumiracoxib, a novel cyclooxygenase-2 selective inhibitor, vs. non-selective non-steroidal anti-inflammatory drugs in an outcomes study of considerably increased size. This paper describes the study's methodology. 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. Randomization was stratified for low-dose aspirin use and age (≤ 64, 65–74, ≥ 75 years). The study was powered to investigate upper gastrointestinal ulcer complications (primary endpoint) in patients not taking aspirin and in the overall study population; other endpoints included cardiovascular, renal and hepatic measures. Conclusions : Therapeutic Arthritis Research and Gastrointestinal Event Trial was designed to provide definitive answers concerning the gastrointestinal safety of Lumiracoxib, addressing the controversial issues arising from outcomes studies with other cyclooxygenase-2 selective inhibitors.
Graham Scott - One of the best experts on this subject based on the ideXlab platform.
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Lack of Effect of Omeprazole or of an Aluminium Hydroxide/Magnesium Hydroxide Antacid on the Pharmacokinetics of Lumiracoxib
Clinical Pharmacokinectics, 2012Co-Authors: Graham Scott, Christine Reynolds, Slavica Milosavljev, Wayne K. Langholff, Magdy Shenouda, Christiane RordorfAbstract:Objective: To evaluate the effects of multiple doses of omeprazole and of a single dose of an aluminium hydroxide/magnesium hydroxide (Al/Mg) antacid on the single-dose plasma pharmacokinetics of Lumiracoxib.
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Pharmacokinetics of Lumiracoxib in Plasma and Synovial Fluid
Clinical Pharmacokinetics, 2004Co-Authors: Graham Scott, Christiane Rordorf, Christine Reynolds, Jyoti Kalbag, Michael Looby, Slavica Milosavljev, Margaret Weaver, John P. Huff, Dennis A. RuffAbstract:Background umiracoxib 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. Design Open-label multiple-dose study evaluating the steady-state pharmacokinetics of Lumiracoxib in plasma and synovial fluid after 7 days of treatment with Lumiracoxib 400mg once daily. Patient population Males and females aged 18–75 years with rheumatoid arthritis, having moderate to significant synovial fluid effusion of the knee. Outcome measures Following a 7-day washout period for previous nonsteroidal anti-inflammatory drugs, 22 patients (17 female, 5 male) received Lumiracoxib 400mg 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 μg/L) was approximately three times higher than the mean value in plasma (155 μg/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. Conclusion 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.
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Lack of Effect of Omeprazole or of an Aluminium Hydroxide/Magnesium Hydroxide Antacid on the Pharmacokinetics of Lumiracoxib
Clinical Pharmacokinetics, 2004Co-Authors: Graham Scott, Slavica Milosavljev, Wayne K. Langholff, Magdy Shenouda, Christine Vinluan Reynolds, Christiane RordorfAbstract:Objective: To evaluate the effects of multiple doses of omeprazole and of a single dose of an aluminium hydroxide/magnesium hydroxide (Al/Mg) antacid on the single-dose plasma pharmacokinetics of Lumiracoxib. Study Design: Open-label, randomised, three-period, crossover study. Population Studied: Healthy subjects aged 18–65 years. Methods: Fourteen subjects who met eligibility criteria were each administered three treatments in random order: (A) Lumiracoxib 400mg as a single oral dose; (B) oral omeprazole 20mg once daily for 4 consecutive days, then Lumiracoxib 400mg as a single oral dose just prior to oral omeprazole 20mg on day 5; and (C) Lumiracoxib 400mg as a single oral dose immediately prior to a 20mL dose of Al/Mg antacid (magnesium hydroxide 800mg and aluminium hydroxide 900mg). The interval between each Lumiracoxib dose was 7 days. Analysis of variance was performed to determine whether Lumiracoxib alone differed from Lumiracoxib plus omeprazole or from Lumiracoxib plus Al/Mg antacid for overall exposure (area under the concentration-time curve from zero to infinity [AUC_∞]) and peak concentration (C_max), with treatment sequence, subject, period and treatment as factors. Ratios of geometric means between Lumiracoxib plus omeprazole and Lumiracoxib plus Al/Mg antacid to Lumiracoxib alone (reference) were calculated for AUC_∞ and C_max. If the mean ratios, with 90% CIs, fell within the interval 0.80–1.25, the treatments were considered equivalent. Results: Arithmetic mean plasma Lumiracoxib concentration-time profiles were similar for all treatments, with a rapid rise in concentration after administration, reaching C_max values (mean ± SD) of 9.24 ± 1.96, 8.81 ± 2.30, and 10.43 ± 3.24 mg/L within 2–3 hours for treatments A, B and C, respectively. AUC_∞ was similar for the three treatments (36.75 ± 7.73, 34.88 ± 8.40 and 35.50 ± 5.72 mg • h/L). All ratios of geometric means with 90% CIs fell within the interval used for establishing bioequivalence, except for the C_max comparison between Lumiracoxib plus Al/Mg antacid and Lumiracoxib alone, which was 1.11 (0.95, 1.31). Conclusion: Coadministration of Lumiracoxib with omeprazole or with an Al/Mg antacid had no clinically significant effect on Lumiracoxib single-dose plasma pharmacokinetics. Lumiracoxib can, therefore, be administered concurrently with either of these agents without need for Lumiracoxib dosage alteration.
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Assessment of Lumiracoxib Bioavailability from Targeted Sites in the Human Intestine Using Remotely Activated Capsules and Gamma Scintigraphy
Pharmaceutical Research, 2004Co-Authors: Ian R. Wilding, Christiane Rordorf, Slavica Milosavljev, Janice Branson, Alyson L. Connor, Polly Carpenter, Graham ScottAbstract:Purpose. To determine the bioavailability and pharmacokinetic profile of Lumiracoxib from different sites in the gastrointestinal tract. Methods. Subjects (11 healthy adult males) were randomized to receive a 100 mg Lumiracoxib dose, via a site-specific radiolabeled delivery capsule, to the stomach (internal reference), proximal small bowel, distal small bowel, or ascending colon. Gamma scintigraphy was used for real-time visualization of capsule location, and a radio- frequency signal was used to activate capsules at target site. Results. Ten subjects completed the study. The mean capsule activation times for the stomach, proximal small bowel, distal small bowel, and ascending colon were 0.22, 1.52, 3.43, and 11.46 h post dose, respectively. Lumiracoxib was well absorbed from the proximal and distal small bowel, with AUC_0-≈ ratios 104% (86, 127)% and 110% (89, 136)%, respectively. The highest C_max (2413 ng/ml) and AUC_0-≈ for Lumiracoxib were in the distal small bowel (6842 ng·h/ml). Effective absorption was observed from the ascending colon, with an AUC_0-≈ ratio of 85% (69, 104)% vs. the reference. Conclusions. Lumiracoxib is rapidly and efficiently absorbed throughout the gastrointestinal tract.
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Lumiracoxib: pharmacokinetic and pharmacodynamic profile when coadministered with fluconazole in healthy subjects.
Journal of clinical pharmacology, 2004Co-Authors: Graham Scott, Slavica Milosavljev, Linda Yih, Ching‐ming Yeh, Aziz Laurent, Christiane RordorfAbstract: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 - ∞ but had no effect on Lumiracoxib mean C m a x . The geometric mean ratio (Lumiracoxib plus fluconazole/ Lumiracoxib alone) for A AUC 0 - ∞ was 1.19 (90% confidence interval [CI] = 1.12, 1.27) and for C m a x 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.
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Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a prospective randomized 13-week study versus placebo and celecoxib.
Clinical rheumatology, 2005Co-Authors: Roy Fleischmann, Dipen Dutta, Eric Sheldon, José A. Maldonado-cocco, Victor S. SloanAbstract:The objective of this study was to evaluate the efficacy, safety and tolerability of Lumiracoxib compared with placebo and celecoxib in patients with osteoarthritis (OA). Following a 3- to 7-day washout period for previous non-steroidal anti-inflammatory drugs, 1600 patients aged ≥18 years with primary knee OA were randomized to receive Lumiracoxib 200 or 400 mg once daily (o.d.), celecoxib 200 mg o.d. or placebo for 13 weeks. Primary efficacy variables were OA pain intensity in the target knee, patient’s global assessment of disease activity and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale and total scores at week 13. Secondary variables included OA pain intensity in the target knee and physician’s and patient’s global assessments of disease activity by visit. Exploratory analysis of responder rates using the Outcomes Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) criteria was performed. Safety and tolerability were assessed. Lumiracoxib was superior to placebo in all primary and secondary variables and was generally similar to celecoxib. There were no statistically significant differences between the two doses of Lumiracoxib. All active treatments were significantly more effective than placebo at weeks 2 and 13 in terms of response to treatment assessed using OMERACT-OARSI criteria. The incidence of adverse events was similar across the groups. Lumiracoxib 200 mg o.d. is a well-tolerated and effective treatment option for OA of the knee, providing pain relief and improved functional status with efficacy superior to placebo and similar to celecoxib. Lumiracoxib demonstrated a tolerability profile similar to placebo and celecoxib.
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Efficacy and tolerability of Lumiracoxib 100 mg once daily in knee osteoarthritis: a 13-week, randomized, double-blind study vs. placebo and celecoxib.
Current medical research and opinion, 2005Co-Authors: Reiner Lehmann, Andreas Kreiss, Marek Brzosko, Petr Kopsa, Ruth Nischik, Helen Thurston, Stephane Litschig, Victor S. SloanAbstract:ABSTRACTObjective: To determine the efficacy and safety of Lumiracoxib for knee osteoarthritis (OA).Methods: This was a 13-week, multicentre, randomized, double-blind, double-dummy, placebo-controlled study. Males or females aged ≥ 18 years with primary knee OA received Lumiracoxib 100 mg od, Lumiracoxib 100 mg od with a loading dose of 200 mg od for the first two weeks, celecoxib 200 mg od, or placebo.Main outcome measures: Co-primary variables, assessed at week 13, were OA pain intensity in the target knee, patient's global assessment of disease activity and the WOMAC total score. Other variables included OMERACT–OARSI responder rates and WOMAC subscale scores. Safety and tolerability were evaluated.Results: All active treatments were superior to placebo for all co-primary variables. No significant differences were observed between any active treatments. Mean reductions from baseline to week 13 for Lumiracoxib 100 mg od, 100 mg od with loading dose, celecoxib and placebo, respectively, were: OA pain int...
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Lumiracoxib in the treatment of osteoarthritis, rheumatoid arthritis and acute postoperative dental pain: results of three dose-response studies
Current medical research and opinion, 2005Co-Authors: Thomas J. Schnitzer, Xavier Gitton, James R. Fricke, Sumedha Jayawardene, Victor S. SloanAbstract:ABSTRACTObjectives: Overview of three dose-response studies demonstrating the efficacy of Lumiracoxib, a novel COX-2 selective inhibitor, for chronic pain associated with osteoarthritis (OA), or rheumatoid arthritis (RA) and acute pain following dental extraction.Methods: OA and RA: 4-week, randomized, placebo- and active-controlled studies of similar design. Patients (OA, n = 583; RA, n = 571) received Lumiracoxib 50 mg, 100 mg or 200 mg twice daily (bid), Lumiracoxib 400 mg once daily (od), diclofenac 75 mg bid or placebo. Dental: 12-h, single-center, randomized, placebo- and active-controlled study. Patients (n = 202) received single oral doses of Lumiracoxib 100 mg or 400 mg, ibuprofen 400 mg or placebo.Main outcome measures: OA: pain intensity (PI) in the target joint (visual analogue scale [VAS]) and WOMAC score at Week 4; RA: overall PI (VAS) and ACR20 response at Week 4; Dental: difference (PID, categorical and VAS) score over 12 h post dose, time to onset of analgesia.Results: Throughout the OA s...
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Efficacy and tolerability of Lumiracoxib in the treatment of osteoarthritis of the knee: a 13-week, randomized, double-blind comparison with celecoxib and placebo.
Clinical therapeutics, 2005Co-Authors: Eric Sheldon, Andre Beaulieu, Zorba Paster, Dipen Dutta, Victor S. SloanAbstract:Abstract Background: Lumiracoxib is a cyclooxygenase-2-selectiveinhibitor developed for the treatment of osteoarthritis (OA), rheumatoid arthritis, and acute pain. Objectives: This study assessed the efficacy and tolerability of Lumiracoxib 100 mg QD compared with celecoxib and placebo in patients with OA of the knee. Methods: In this 13-week, double-blind, double-dummy,placebo-controlled, parallel-group study, patients with primary OA of the knee and pain intensity in the target knee a40 mm on a 100-mm visual analog scale after a 3- to 7-day washout of nonsteroidal anti-inflammatory drugs were randomized to receive Lumiracoxib 100 mg QD, Lumiracoxib 100 mg QD with a loading dose of Lumiracoxib 200 mg QD for the first 2 weeks, celecoxib 200 mg QD, or placebo. Three primary efficacy variables were assessed at the end of the study: pain intensity in the target knee, the patient's global assessment of disease activity, and functional status (Western Ontario and McMaster Universities Osteoarthritis Index total score). In addition, the treatment response was assessed using the Outcome Measures in Clinical Trials-Osteoarthritis Research Society International (OMERACT OARSI) criteria. The safety profile and tolerability of all treatments were also examined. Results: The study enrolled 1551 patients (primarily white; 62% female; mean age, 60.5 years): 391 were randomized to receive Lumiracoxib 100 mg QD, 385 Lumiracoxib 100 mg QD with a loading dose, 393 celecoxib 200 mg QD, and 382 placebo. Treatment groups were closely balanced at baseline with respect to demographic and disease characteristics. Lumiracoxib was superior to placebo ( P P P P P Conclusion: In this population of patients with OA of the knee, Lumiracoxib 100 mg QD was of similar efficacy to celecoxib 200 mg QD and had similar tolerability to placebo.
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Efficacy of Lumiracoxib in osteoarthritis: a review of nine studies.
The Journal of international medical research, 2005Co-Authors: Francis Berenbaum, Gerhard Krammer, Alan Moore, J Zacher, J P Brown, Joachim Grifka, D Dutta, Victor S. SloanAbstract:Lumiracoxib is a cyclooxygenase-2 selective inhibitor in development for the treatment of osteoarthritis (OA), rheumatoid arthritis and acute pain. We reviewed nine clinical studies of 1 − 52 weeks' duration demonstrating the efficacy of Lumiracoxib in OA. Male and female patients aged ≥ 18 years with primary OA of the hand, hip or knee received Lumiracoxib, placebo or active comparators (diclofenac, celecoxib or rofecoxib). Lumiracoxib provided consistent reductions in OA pain intensity and improvements in the patient's global assessment of disease activity and functional status (assessed using the Western Ontario and McMaster Universities Osteoarthritis Index questionnaire or the Australian/Canadian OA Hand Index). These results were superior to placebo and similar to the active comparators tested. In addition, Lumiracoxib was consistently superior to placebo and generally similar to active comparators in terms of the new Outcome Measures in Clinical Trials and Osteoarthritis Research Society Internatio...
