ABSTRACT
OBJECTIVES: Blockade of N-methyl-D-aspartate receptors containing the NR2B subunit has been shown to be therapeutic in animal models of Parkinson disease (PD). However, findings with investigational NR2B receptor antagonists in PD patients have been mixed. The objective of this study was to evaluate the effects of the NR2B selective N-methyl-D-aspartate receptor antagonist MK-0657 on levodopa-induced dyskinesias and motor symptoms in PD patients. METHODS: A randomized, double-blind, single-dose, 2-period crossover study was conducted in 22 patients with PD and levodopa-induced peak-dose dyskinesias. Patients received oral MK-0657 (7 mg) or placebo, in randomized order, on each of 2 test days. On both days, levodopa was administered as a 2-hour intravenous infusion at greater than or equal to 1 mg/kg per hour with frequent assessments of dyskinesia, motor function, and pharmacokinetics. RESULTS: MK-0657 7 mg had no significant effect on dyskinesias (difference versus placebo in modified Abnormal Involuntary Movement Scale mean change from baseline area under the curve over 5 hours, -2.3; 95% confidence interval, -5.1 to 0.4) or motor function (difference versus placebo in Unified Parkinson's Disease Rating Scale Part III mean change from baseline area under the curve over 5 hours, 13.9; 95% confidence interval, -1.7 to 29.5). MK-0657 7 mg achieved the target mean maximum plasma concentration of 400 nM. CONCLUSIONS: These data suggest that a single dose of MK-0657 7 mg is not effective in improving levodopa-induced dyskinesias and motor symptoms in PD patients. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT00505843.
Subject(s)
Antiparkinson Agents/adverse effects , Dyskinesia, Drug-Induced/drug therapy , Levodopa/adverse effects , Parkinson Disease/drug therapy , Piperidines/administration & dosage , Pyrimidines/administration & dosage , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Aged , Antiparkinson Agents/administration & dosage , Antiparkinson Agents/blood , Cross-Over Studies , Double-Blind Method , Drug Therapy, Combination , Dyskinesia, Drug-Induced/blood , Dyskinesia, Drug-Induced/diagnosis , Dyskinesias/blood , Dyskinesias/diagnosis , Dyskinesias/drug therapy , Female , Humans , Levodopa/administration & dosage , Levodopa/blood , Male , Middle Aged , Parkinson Disease/blood , Parkinson Disease/diagnosis , Piperidines/blood , Pyrimidines/blood , Receptors, N-Methyl-D-Aspartate/blood , Treatment OutcomeABSTRACT
To investigate the influence of modifying in vivo cytochrome P450 3A (CYP3A) activity on the pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, and of etoricoxib administration on CYP3A activity, a 3-part, randomized, crossover study was conducted in 3 panels of healthy volunteers. In part I, 8 subjects were administered a single dose of 60 mg etoricoxib alone and following daily doses of 400 mg ketoconazole, a known strong inhibitor of CYP3A. In part II, 8 different subjects were administered a single dose of 60 mg etoricoxib alone and following daily doses of 600 mg rifampin, a known strong inducer of CYP3A. In parts I and II, plasma samples were collected following each etoricoxib dose and analyzed for etoricoxib. In part III, 8 different subjects were administered 120 mg etoricoxib or placebo once daily for 11 days, and the erythromycin breath test was administered on day 11 of each period. Coadministration of etoricoxib with daily doses of ketoconazole resulted in an average 43% increase in etoricoxib AUC; based on previous studies, this increase would not be expected to have any clinically meaningful effect. In contrast, coadministration of etoricoxib with daily doses of rifampin had a potentially clinically important effect on etoricoxib pharmacokinetics (average 65% decrease in etoricoxib AUC). Etoricoxib had no effect on hepatic CYP3A activity, as assessed by the erythromycin breath test.
Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Sulfones/administration & dosage , Sulfones/pharmacokinetics , Adult , Analysis of Variance , Confidence Intervals , Cross-Over Studies , Cytochrome P-450 CYP3A , Enzyme Activation/drug effects , Enzyme Activation/physiology , Etoricoxib , Female , Humans , Male , Pyridines/blood , Sulfones/bloodABSTRACT
BACKGROUND: Patients experiencing acute pain after surgery, including dental surgery, often require analgesia. Ideally, the chosen analgesic should have a rapid onset and sustained effect. Etoricoxib is a new cyclooxygenase-2-selective inhibitor that has demonstrated analgesic efficacy in the treatment of acute pain with a rapid onset and long-lasting pain relief. OBJECTIVE: The goal of this study was to determine the analgesic effect of single oral doses of etoricoxib 60, 120, 180, and 240 mg compared with placebo in the treatment of pain after dental surgery. Ibuprofen was used as an active control. METHODS: This was a randomized, double-blind, parallel-group, single-dose, placebo- and active comparator-controlled study performed at a single center. It consisted of 3 visits (prestudy, treatment, and poststudy). Eligible patients were aged > or =16 years with moderate or severe pain after surgical extraction of > or =2 third molars, of which > or =1 was an impacted mandibular molar. Patients were assessed over 24 hours and reported pain intensity and pain relied at 14 predefined time points. Plasma samples for a pharmacokinetic/pharmacodynamic analysis were collected from a subset of patients at baseline and the 14 predefined time points. The end points included total pain relief over 8 hours (TOPAR8, the primary end point), sum of pain intensity difference over 8 hours, patient's global evaluation of treatment, median time to onset of pain relief (2-stopwatch method), peak pain relief, and duration of analgesic effect (median time to use of rescue medication). Adverse events were collected up to 14 days postdose. RESULTS: Three hundred ninety-eight (63.1% women, 36.9% men; mean age, 21.1 years; 72.1% white, 27.9% other; mean number of third molars removed, 3.5; 65.2% experiencing moderate pain) were randomly allocated to receive etoricoxib 60 mg (n = 75), etoricoxib 120 mg (n = 76), etoricoxib 180 mg (n = 74), etoricoxib 240 mg (n = 76), ibuprofen 400 mg (n = 48), and placebo (n = 49). All active treatments had significantly greater overall analgesic effect (TOPAR8) compared with placebo (P < or 0.001). Patients who received etoricoxib 120 and 180 mg had significantly higher TOPAR8 scores than those who received etoricoxib 60 mg ( P < = 0.001) and ibuprofen (P < 0.05 etoricoxib 120 mg; P < or = 0.001 etoricoxib 180 mg). Least-squares mean TOPAR8 scores for etoricoxib 60, 120, 180, and 240 mg, ibuprofen, and placebo were 16.0, 22.0, 23.5, 20.7, 18.6, and 5.2, respectively. The median time to onset of analgesia was 24 minutes for etoricoxib 120, 180, and 240 mg, and 30 minutes for etoricoxib 60 mg and ibuprofen. There were no significant differences in the onset of analgesia between etoricoxib 120, 180, and 240 mg and ibuprofen. The duration of analgesic effect was >24 hours for etoricoxib 120, 180, and 240 mg, and 12.1 hours for etoricoxib 60 mg. The duration of effect was significantly longer with all 4 etoricoxib doses compared with ibuprofen (10.1 hours; P < 0.05 etoricoxib 60 mg; < or = 0.001etoricoxib 120, 180, and 240 mg) and compared with placebo (2.1 hours; P < = 0.001). In the pharmacokinetic/pharmacodynamic analysis (n approximately 120), there was a linear relationship between plasma etoricoxib concentrations and pain relief scores up to the maximum observed concentration, followed by a decline in plasma concentrations with persistent analgesia. The most common adverse events were postextraction alveolitis and nausea. CONCLUSIONS: In this dose-ranging study, etoricoxib 120 mg was determined to be the minimum dose that had maximal efficacy in patients with moderate to severe acute pain associated with dental surgery. Both etoricoxib and ibuprofen were generally well tolerated.
Subject(s)
Isoenzymes/antagonists & inhibitors , Pain, Postoperative/drug therapy , Pyridines/administration & dosage , Pyridines/therapeutic use , Sulfones/administration & dosage , Sulfones/therapeutic use , Tooth Extraction/adverse effects , Adolescent , Adult , Cyclooxygenase 2 , Dose-Response Relationship, Drug , Double-Blind Method , Etoricoxib , Female , Humans , Male , Membrane Proteins , Pain, Postoperative/etiology , Prostaglandin-Endoperoxide Synthases , Pyridines/pharmacokinetics , Sulfones/pharmacokineticsABSTRACT
The effect of renal insufficiency on the pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, was examined in 23 patients with varying degrees of renal impairment (12 moderate [creatinine clearance between 30 and 50 mL/min/1.73 m2], 5 severe [creatinine clearance below 30 mL/min/1.73 m2], and 6 with end-stage renal disease requiring hemodialysis) following administration of single 120-mg oral doses of etoricoxib. Even the most severe renal impairment was found to have little effect on etoricoxib pharmacokinetics. The low recovery of etoricoxib in dialysate (less than 6% of the dose) supports that hemodialysis also has little effect on etoricoxib pharmacokinetics, and binding of etoricoxib to plasma proteins was generally unaffected by renal disease. Single doses of etoricoxib were generally well tolerated by patients with renal impairment. Based on pharmacokinetic considerations, dosing adjustments are not necessary for patients with any degree of renal impairment. However, because patients with advanced renal disease (creatinine clearance below 30 mL/min/1.73 m2) are likely to be very sensitive to any further compromise of renal function, and there is no long-term clinical experience in these patients, the use of etoricoxib is not recommended in patients with advanced renal disease.
Subject(s)
Cyclooxygenase Inhibitors/pharmacokinetics , Kidney Failure, Chronic/metabolism , Pyridines/pharmacokinetics , Sulfones/pharmacokinetics , Administration, Oral , Adult , Aged , Area Under Curve , Biological Availability , Clinical Trials as Topic , Etoricoxib , Female , Half-Life , Humans , Kidney Failure, Chronic/therapy , Male , Metabolic Clearance Rate , Middle Aged , Protein Binding , Renal DialysisABSTRACT
OBJECTIVE: Rofecoxib suspension is a formulation developed to increase the convenience of rofecoxib therapy for patients who have difficulty swallowing tablets. This open-label, two-part study compared the single-dose pharmacokinetics of rofecoxib tablets and rofecoxib suspension in healthy subjects. DESIGN AND STUDY PARTICIPANTS: Part I was a two-period crossover study that assessed the bioequivalence of the 12.5mg/5mL rofecoxib suspension and the 12.5mg rofecoxib tablet in 24 healthy subjects (12 men and 12 women). Part II was a crossover study in 24 additional healthy subjects (12 men and 12 women) that determined the bioequivalence of the rofecoxib 25mg/5mL suspension and the 25mg rofecoxib tablet. RESULTS: No clinically meaningful differences between rofecoxib tablet and suspension were apparent with respect to the rofecoxib area under the concentration-time curve from time zero to infinity (AUC(0-infinity)) and maximum plasma concentration (C(max)), the primary measures of bioequivalence. At the 12.5mg and 25mg doses, the 90% CI for the geometric mean ratio (suspension/tablet) of both AUC(0-infinity) and C(max) fell within the prespecified interval for bioequivalence (0.80-1.25). CONCLUSIONS: The rofecoxib suspension is bioequivalent to the rofecoxib tablet at single oral doses of 12.5mg and 25mg in healthy volunteers. The convenience and ease of administration of rofecoxib suspension may translate into increased compliance with therapy compared with a conventional solid tablet formulation, particularly for elderly patients.