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BRIEF REPORT/DRUG INTERACTIONS |
From Merck Research Laboratories, Merck & Co Inc, Rahway, New Jersey (Dr Schwartz, Dr Agrawal, Ms Kher, Dr DeSmet, Dr Cavanaugh, Mr Ebel, Ms Merschman, Dr Wagner); and the Center for Clinical Pharmacology, Aster-Cephac, Paris, France (Dr Guillaume).
Address for correspondence: Jules I. Schwartz, PharmD, MPH, Merck Research Laboratories, 126 East Lincoln Avenue, PO Box 2000, RY34-A552, Rahway, NJ 07065-0900.
Key Words: Etoricoxib • antacids • cyclooxygenase 2
Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most widely prescribed classes of therapeutic agents. Although NSAIDs are highly effective for the relief of pain and inflammation associated with arthritic conditions,1,2 the use of traditional NSAIDs, which inhibit both cyclooxygenase isoenzymes (COX-1 and COX-2), is often limited by their gastrointestinal (GI) toxicity.3 In addition to an elevated risk of serious GI clinical events such as upper GI perforations, ulcers, and bleeds, up to 60% of patients on traditional NSAID therapy often complain of nuisance symptoms such as dyspepsia that are often not related to GI mucosal damage.4,5 This can lead to a significant number of patients being prescribed gastroprotective agents (GPAs) or switching from their current NSAID therapy.6-10
Etoricoxib and other COX-2 selective NSAIDs were specifically developed to provide anti-inflammatory and analgesic efficacy with a reduced risk of GI toxicity and nuisance symptoms.11-14 However, gastric adverse effects may still occur.13,15
Antacids containing calcium, magnesium, or aluminum salts are frequently used for symptomatic relief of dyspepsia and other gastric disorders,10 and their widespread use supports a rationale to evaluate effects on the systemic exposure of etoricoxib. Here we report the results of a 4-period, 2-part, open-label study designed to assess the intrasubject variability of etoricoxib pharmacokinetics in healthy subjects treated concomitantly with antacids containing salts of calcium, magnesium, and aluminum.
METHODS
Subjects
Healthy men and women between the ages of 40 and 65 years were eligible to participate. Subjects were required to be nonsmokers and to be within 30% of their ideal body weight.16 Female subjects of child-bearing potential were determined to be in a non-gravid state at prestudy (and predose) using a human ß-chorionic gonadotropin-based immunoassay. Subjects were instructed to abstain from drinking grapefruit juice to avoid altered metabolism of etoricoxib attributable to inhibition of CYP3A4 activity, drinking excess alcohol, or participating in strenuous physical activity for the duration of the study and follow-up period.
The study protocol was approved by the local institutional review board, Comite Consultaif de Protection des Personnes dans la Recherche Biomedicale, Paris, France. All subjects provided written informed consent prior to study participation.
Study Design
This was a 4-period, 2-part, open-label study (Protocol 31) enrolling 12 subjects 40 to 65 years of age. Subject recruitment took into account the need to balance the distribution across the desired age range so that half of the subjects would be 40 to 54 years old and the other half would be 55 to 65 years old, with a minimum of at least 2 of either gender in each age group. These 2 age groups, however, were not used for any formal statistical comparison.
The primary objective of this study (part 1) was to determine whether the plasma concentration-time profile of etoricoxib 120 mg is affected by oral coadministration of antacids containing either calcium carbonate or a mixture of magnesium and aluminum hydroxide. This was accomplished by comparing the area under the plasma concentration-time curve from time 0 to infinity (AUC0-
), peak plasma concentration (Cmax), time of occurrence of peak plasma concentration (Tmax), and apparent terminal half-life (t
) of etoricoxib in the presence and absence of antacids. For the second objective (part 2), we estimated the intrasubject variability of the AUC0-, Cmax, Tmax, and t of etoricoxib from paired data for individual subjects following 2 separate administrations of oral etoricoxib 120 mg without antacid coadministration.
Part 1 was a 3-period, balanced, randomized, crossover study in which subjects were administered single oral doses of 120 mg of etoricoxib alone, combined with 10 mL of calcium carbonate (1250 mg per 5 mL) or 20 mL of a suspension containing 200 mg of magnesium hydroxide and 225 mg of aluminum hydroxide per 5 mL. In part 2, subjects were administered a second single dose of 120 mg etoricoxib alone to estimate intrasubject pharmacokinetic variability.
All etoricoxib doses, when given alone, were administered with 240 mL of water. When taken with the antacid, etoricoxib was taken with 120 mL of water immediately followed by the antacid suspension and then by 120 mL of water. All doses were administered following an overnight fast. A standard drink and meal were provided for all subjects at 2 and 4 hours postdose, respectively. There was a 10-day washout interval between etoricoxib doses.
Heparinized blood samples for analysis of etoricoxib concentrations were collected predose and at prespecified intervals from 0.5 to 168 hours postdose in each period. Safety and tolerability were assessed by physical examinations, vital signs, hematology, routine serum chemistry, urinalysis, adverse events, and 12-lead electrocardiogram measurements.
Analytical Methods
Etoricoxib concentrations in plasma were determined as previously described.17 The lower limit of accurate measurement in plasma was 0.5 ng/mL. The within-day coefficient of variation of the assay was typically less than 3.5% across the concentration range of 0.5 to 80 ng/mL. The average between-day coefficient of variation was less than 8%.
Study Drugs
Antacid suspension was administered by oral syringe to ensure a standardized and accurate dose. Each antacid was used at its recommended dose. The dose of calcium carbonate suspension (Roxane Laboratories Inc, Columbus, Ohio) had an acid neutralizing capacity (ANC) of 50 mEq. The dose of magnesium and aluminum hydroxide suspension (Ciba Self-Medication Inc, Woodbridge, NJ) had an ANC of approximately 53 mEq. All antacid doses came from the same manufactured lot of the respective antacid. Etoricoxib tablets (60 mg) were supplied by Merck & Co, Inc (Whitehouse Station, NJ). The 120-mg etoricoxib dose (2 x 60-mg tablets) is the maximum dose approved for use for the short-term management of acute pain.11,18
Pharmacokinetics
Plasma etoricoxib concentrations and the actual sampling times relative to the etoricoxib dose were used to estimate the pharmacokinetic parameters of AUC0-, Cmax, Tmax, and t for each treatment in each subject. Maximum plasma concentrations and Tmax were obtained by inspection of the individual subject's data. The t was estimated from the best-fit parameters of a single exponential to the terminal log-linear portion of the plasma concentration-time curve. The best-fit parameters were obtained using nonlinear regression with a Simplex algorithm19 using a weight of 1. The AUC0- was calculated using the linear trapezoidal method up to the last measured concentration, and the extrapolated area was estimated by dividing the last measured concentration by the value of the t estimated for that administration.
Statistical Analyses
An analysis of variance model (ANOVA) appropriate for a 3-period, crossover design with terms for subject, treatment, and period was used to analyze the pharmacokinetics of etoricoxib administered with and without the respective antacid products (part 1). Intrasubject variability was determined by the analysis of paired data for subjects following the repeated oral doses of etoricoxib 120 mg using an ANOVA model containing factors for subject and treatment. In addition, 95% confidence intervals (CIs) using the 
2 distribution were also determined for within-subject variability, that is, coefficient of variation (approximate SD on the log scale) on a log scale (part 2).
The period factor, a test for carryover, was not significant and therefore was not included in the final ANOVA model. Prior to statistical analysis, the AUC0- and Cmax values were adjusted for the assayed potency of the formulation. A log transformation was applied to the AUC0- and Cmax data. Other transformations (ie, rank, inverse) were also applied to the pharmacokinetic data as appropriate. The normality assumption of the ANOVA model was tested using the Shapiro-Wilks statistic, and the homogeneity of variance assumption was tested using the Levene test; the assumptions were generally satisfied. Ninety percent CIs, based on the t distribution, were computed on the geometric mean ratios (GMRs) of the respective pharmacokinetic values with and without antacid, and the resulting ratios were compared with the prespecified clinically meaningful bounds for determination of similarity (ie, 0.50-2.00). The upper bound of 2.00 was chosen because etoricoxib doses of up to 240 mg were well tolerated in initial pharmacokinetic studies of the drug.17 The lower confidence bound of 0.5 was chosen because 60 mg was the lowest clinical dose at the time for the chronic treatment of osteoarthritis.20-25 Also, it was assumed that less than a 2-fold change in etoricoxib plasma concentrations was unlikely to be associated with a clinically meaningful effect with respect to safety and efficacy.
The sample size of this study (n = 12) provided at least 80% probability for the 90% CI to be within the interval of 0.50 to 2.00 if the true GMR of etoricoxib's AUC0- in the presence and absence of antacid was within the CI of 0.56 to 1.8.
RESULTS
Subjects
Twelve subjects (5 men and 7 women) were enrolled in the study; all were Caucasian, and all successfully completed the study. The mean (range) age, weight, and height were 52.2 (40-62) years, 69.8 (53.2-86.3) kg, and 176 (150-179) cm, respectively.
Pharmacokinetics
Mean plasma etoricoxib concentrations are shown over 168 hours in Figure 1. The secondary peaks observed in the plasma concentration-time profile are consistent with observations from a previous report,17 and their origin is unknown. Differences in Cmax were apparent with the antacids; however, the GMRs of AUC0- approximated 1.0 and were well within the prespecified 90% confidence bounds for similarity (Table I).
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Calcium carbonate coadministration resulted in a small but significant reduction of Cmax compared with etoricoxib alone (Table I). Following coadministration of magnesium and aluminum hydroxide, there was a small, statistically insignificant decrease in the Cmax of etoricoxib. However, the GMRs for Cmax relative to etoricoxib alone were 0.77 (90% CI, 0.67-0.89) and 0.85 (90% CI, 0.74-0.97) for calcium carbonate and for magnesium and aluminum hydroxide, respectively, and were within the prespecified CI for similarity.
The mean Tmax values were similar in all 3 treatment groups: 1.6 (90% CI, 1.13-2.04), 1.6 (90% CI, 1.34-1.83), and 1.8 (90% CI, 1.62-1.96) hours for etoricoxib alone, with calcium carbonate, and with magnesium and aluminum hydroxide, respectively. No significant differences were observed for observed t values (mean [SD]): etoricoxib alone (20.7 [7.8] hours), with calcium carbonate (21.7 [6.3] hours), and with magnesium and aluminum hydroxide (20.7 [6.6] hours), respectively.
Intrasubject Variability
The coefficients of variation for intrasubject variability for etoricoxib AUC0- and Cmax following repeat treatment with 120 mg of etoricoxib were 10.2% (95% CI, 7.2%-17.3%) and 15.6% (95% CI, 11.1%-26.6%), respectively. The GMRs for AUC0- and Cmax comparing the first and second dose of etoricoxib were 1.04 (90% CI, 0.96-1.12) and 0.91 (90% CI, 0.80-1.01), respectively. The within-subject standard deviations for Tmax and t were 0.17 hours (95% CI, 0.12-0.30) and 1.88 hours (95% CI, 1.33-3.20), respectively.
Safety
All subjects were included in the evaluation of safety. Six adverse experiences occurred in 3 subjects, none of which was serious. Five of the adverse experiences were rated as possibly drug related by the investigator. One subject reported 3 instances of mild, loose stools approximately 4 to 6 hours following each of the 3 treatment regimens. One subject reported mild epigastric pain approximately 11.5 hours after receiving etoricoxib and magnesium and aluminum hydroxide. One subject reported mild diarrhea approximately 1 day following a dose of etoricoxib only. No subject discontinued because of a clinical adverse experience. All adverse experiences were transient and mild or moderate in intensity. No laboratory adverse experiences were reported.
DISCUSSION
The results of this study demonstrate that the antacids calcium carbonate and magnesium and aluminum hydroxide had no clinically meaningful effects on the pharmacokinetic profile of etoricoxib in healthy volunteers based on the prespecified criteria. The 90% CIs for the GMRs of AUC0- in the presence of each antacid were close to 1.0 and were within the prespecified confidence bounds of 0.50 and 2.00 for similarity. However, Cmax values were reduced by 23% and 15% by calcium carbonate and magnesium and aluminum hydroxide, respectively. Based on the dose-response profile for efficacy observed with chronic dosing with etoricoxib in patients with rheumatic diseases,22,25 it is unlikely that this decrease in Cmax is clinically important. The pharmacokinetic profile of etoricoxib administered alone in this study was consistent with a previously published report.17 The intrasubject pharmacokinetic variability of etoricoxib is very low.
Although the risk of dyspepsia with etoricoxib is reduced relative to traditional NSAIDs, such symptoms may occur.13,15 Coadministration of etoricoxib with the antacids calcium carbonate or magnesium and aluminum hydroxide has no clinically meaningful effect on etoricoxib single-dose pharmacokinetics.
ACKNOWLEDGEMENTS
We thank Dr William Taggart for his assistance in preparing the draft manuscript.
Financial disclosure: This study was supported by Merck Research Laboratories.
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