Sumiko Shingo

Renal effects of etoricoxib and comparator nonsteroidal anti-inflammatory drugs in controlled clinical trials

BACKGROUND Based on the experience with selective cyclooxygenase (COX)-2 inhibitors, including rofecoxib, valdecoxib, and celecoxib, it was anticipated that etoricoxib, a new selective COX-2 inhibitor, would display mechanism-based, dose-dependent renal adverse effects (AEs) similar to those observed with nonselective non-steroidal anti-inflammatory drugs (NSAIDs) in long-term treatment. OBJECTIVE The present analysis examined pooled safety data from the etoricoxib clinical development program with the aim of comparing the renal AE profiles of etoricoxib 60, 90, and 120 mg/d with those of approved therapeutic dosages of the comparator nonselective NSAIDs, naproxen 1000 mg/d and ibuprofen 2400 mg/d, and with that of placebo. METHODS The etoricoxib program database included data from 8 placebo-controlled Phase III studies of osteoarthritis, rheumatoid arthritis, and chronic low back pain. As part of the program-wide assessment of etoricoxib, the investigator-reported incidence of and discontinuations due to renal AEs, including hypertension, lower-extremity edema (LEE), elevated serum creatinine concentration (SCC), and congestive heart failure (CHF) were examined. RESULTS Data from 4770 patients were included in the analysis. Most patients were women (69.0%-80.3%), and most were white (68.0%-83.3%). The mean (SD) age at baseline ranged from 53.6 (12.1) to 62.2 (8.4) years. Overall, the incidence of renal AEs was low and generally similar between the active-treatment groups. In the placebo; etoricoxib 60-, 90-, and 120-mg; naproxen, and ibuprofen groups, the incidences of hypertension were 2.0%, 4.0%, 3.4%, 4.7%, 2.9%, and 6.6%, respectively, and the incidences of LEE were 1.9%, 3.2%, 1.5%, 1.3%, 2.3%, and 1.8%, respectively. The only significant difference found was the incidence of hypertension with etoricoxib 90 mg/d versus that with placebo (P=0.001); however, the rates of hypertension observed with etoricoxib at any dosage were not clinically meaningfully different versus comparator NSAIDs. Also, LEE was rarely of clinical significance with etoricoxib or comparator NSAIDs; related discontinuations were infrequent in all treatment groups. In addition, the incidences of elevated SCC and CHF were low among active-treatment groups (0.0% to 0.8% and 0.0% to 0.2%, respectively). CONCLUSIONS Based on this combined data review, the risks for renal AEs (i.e., hypertension, LEE, elevated SCC changes, and CHF) with etoricoxib 60, 90, and 120 mg/d were low, with a shallow dose response, and were generally similar to those found with the comparator NSAIDs naproxen 1000 mg/d and ibuprofen 2400 mg/d.

The analgesic effect of etoricoxib relative to that of two opioid-acetaminophen analgesics: a randomized, controlled single-dose study in acute dental impaction pain

ABSTRACT Background: To compare the analgesic effect of single doses of etoricoxib 120 mg, oxycodone/acetaminophen 10 mg/650 mg and codeine/acetaminophen 60 mg/600 mg in acute pain using the dental impaction model. Methods: In this randomized, double-blind, placebo-controlled, parallel-group study, patients reported pain intensity and pain relief (16 times) and global scores (twice) during a 24-h period. The primary endpoint was the overall analgesic effect, total pain relief over 6 h (TOPAR6). Other endpoints were patient global evaluation, time to onset (2-stopwatch method), duration of analgesic effect (median time to and amount of rescue medication use). Tolerability was evaluated by overall and opioid-related (nausea and vomiting) adverse experiences. Results: 302 patients (mean age 23; 63% women; 63 % White) were randomized to etoricoxib 120 mg, oxycodone/acetaminophen 10 mg/650 mg, codeine/acetaminophen 60 mg/600 mg, and placebo (2:2:1:1). Etoricoxib demonstrated significantly greater overall analgesic efficacy (TOPAR6) (13.2 units) versus oxycodone/acetaminophen (10.2 units); and codeine/acetaminophen (6.0 units); p < 0.001 for all. All active treatments were superior to placebo. Median time to onset was significantly ( p < 0.001) shorter for oxycodone/acetaminophen (20 min) and numerically but not significantly shorter ( p = 0.259) for codeine/acetaminophen (26 min) compared with etoricoxib (40 min). Etoricoxib (24 h) had a significantly longer lasting analgesic effect than oxycodone/acetaminophen (5.3 h), codeine/acetaminophen (2.7 h), and placebo (1.7 h) ( p < 0.001 for all). Etoricoxib patients experienced fewer clinical adverse experiences than patients on oxycodone/acetaminophen and codeine/acetaminophen, specifically, significantly ( p < 0.05) fewer episodes of nausea. Conclusion: Etoricoxib 120 mg provided superior overall analgesic effect with a smaller percentage of patients experiencing nausea versus both oxycodone/acetaminophen 10 mg/650 mg and codeine/acetaminophen 60 mg/600 mg.

Blockade of leukotriene production by a single oral dose of MK-0591 in active ulcerative colitis

5‐Lipoxygenase products of arachidonic acid metabolism are thought to play a central role in the secondary amplification of the inflammatory response in a number of human inflammatory diseases, such as ulcerative colitis. MK‐0591 (3‐(1((4‐chlorophenyl)methyl)‐3((1,1‐dimethyl‐ethyl)thio)‐5(quinolin‐2ylmethyl‐oxy)‐1H‐indol‐2yl)‐2,2‐dimethyl‐propanoate) exerts its effect by binding to the 5‐lipoxygenase activating protein, thereby inhibiting the translocation and activation of 5‐lipoxygenase.

Effect of montelukast on single-dose theophylline pharmacokinetics.

The effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist in development for treatment of asthma, on single-dose theophylline plasma concentrations was studied in three separate clinical trials. Montelukast was evaluated at 10 mg once daily (the clinical dosage), 200 mg once daily, and 600 mg (200 mg three times daily). At the clinical dosage, montelukast did not change single-dose theophylline plasma concentration in a clinically important manner. The geometric mean ratios for theophylline area under the plasma concentration versus time curve (AUC0) (0.92) and maximal plasma concentration (Cmax) (1.04) were well within the predefined and generally accepted bioequivalence range of 0.80 and 1.25. Montelukast decreased theophylline Cmax by 12% and 10%, AUC0 by 43% and 44%, and elimination half-time by 44% and 39% at 200 mg/d (oral and intravenous, respectively), and at 600 mg/d, montelukast decreased theophylline Cmax by 25%, AUC0 by 66%, and elimination half-time by 63%. These results show that montelukast at the clinical dosage did not change theophylline pharmacokinetics in a clinically important manner, but at 20− to 60-fold higher dosages, montelukast significantly reduced the theophylline pharmacokinetics parameters; an apparent dosage dependence is suggested.

Pharmacodynamics and Dose‐Response Relationship of Famotidine: A Double‐Blind Randomized Placebo‐Controlled Trial

The dose‐response relationship of oral famotidine at doses up to 10 mg was evaluated in 10 healthy male subjects to assess the extent and duration of inhibition of meal‐stimulated intragastric acid secretion. Each subject received single oral administrations of famotidine 0.5, 2.5, 5.0, and 10.0 mg and placebo in a double‐blind, randomized, crossover fashion. Intragastric pH was measured every 4 seconds for 24 hours and expressed as the mean pH for each 10‐minute interval. Standard high‐protein meals were provided 1 hour before each dose of study drug and at 3 and 9 hours postdose. The mean intragastric pH was significantly higher after famotidine doses 2.5, 5.0, and 10.0 mg than after placebo at times 2.5 to 3.0,1.8 to 3.2, and 1.7 to 4.2 hours postdose, respectively. There were no significant differences in mean pH seen between famotidine 0.5 mg versus placebo. The range of the pH means between 1.7 and 3.2 hours postdose was placebo (1.0 to 1.3), famotidine 0.5 mg (1.1 to 1.4), 2.5 mg (1.4 to 1.7), 5.0 mg (1.7 to 2.1), and 10.0 mg (2.0 to 2.3). There was a statistically significant linear dose‐response relationship between famotidine dose and intragastric pH between 1.7 and 3.8 hours and from 6.3 to 8.7 hours after ingestion.

Lovastatin does not affect oral glucose tolerance in hypercholesterolemic patients

In 15 non‐diabetic Type II hypercholesterolemic patients, the effect of 80 mg lovastatin daily on oral glucose tolerance was investigated. Using a randomized, double‐blind, two‐panel, parallel design, patients on a low cholesterol diet received lovastatin (n=7) or placebo (n=8) for 6 weeks. After 6 weeks of treatment, patients receiving lovastatin had a significant reduction in total cholesterol (30%), LDL‐cholesterol (36%), and triglycerides (26%). Time courses of plasma glucose and serum insulin changes from baseline after the oral glucose tolerance test were evaluated by AUC. No statistically significant differences were observed in the AUC of changes from baseline between treatment groups or within either treatment group at prestudy, 6 weeks, and poststudy. No patient had a clinically important laboratory or clinical drug‐related adverse effect during the study. This study demonstrated that short‐term administration of 80 mg lovastatin daily effectively lowers cholesterol without having adverse effects on oral glucose tolerance.

A Standardized Composite Clinical Score for Inhaled Corticosteroids Taper Studies in Asthma

Current asthma treatment guidelines recommend a reduction in inhaled corticosteroid (ICS) doses when appropriate. However, no standardized taper protocols are available to guide ICS tapering in clinical trials or in general practice. This study was designed to determine the safety and effectiveness of tapering the ICS dase in asthmatic patients using specific tapering and rescue protocols. Twenty-two clinically stable asthmatic patients on moderate-to-high doses of ICS were studied. Patients were given either montelukast (10 mg daily) or placebo for 8 weeks and evaluated every 2 weeks. A composite clinical score (0 to 3) comprising lung function, symptoms, and “as-needed” β-agonist use was calculated at each visit. Based on this score, the ICS dose was either tapered, increased, or maintained at each visit. The minimum ICS dose that maintained clinical stability was defined as the last tolerated dose. The results showed that mean percent change from baseline (1523 μg/day, SD = 536) in the last tolerated dose was 49.8% (SD = 37.4). Sixteen patients tolerated at least one taper; of these, 12 tolerated 2 or more tapers. Seven patients tapered completely off ICS. In contrast, six patients did not tolerate a single taper. Ten patients required rescue from mild worsening with an increase in ICS dose, of which nine were successful and one achieved stability with a second ICS dose increase two weeks later. Overall, patients remained clinically stable during tapering. It is concluded that tapering of ICS guided by the clinical composite score was well tolerated. The rescue protocol was effective in restabilizing patients. The results of this study thus support the use of a composite clinical score in larger clinical trials.