Single‐ and Multiple‐Dose Pharmacokinetics of Etoricoxib, a Selective Inhibitor of Cyclooxygenase‐2, in Man

Abstract

The single- and multiple-dose pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, were examined in two clinical studies. Single-dose pharmacokinetics--including dose proportionality, absolute bioavailability of the highest dose-strength (120-mg) tablet, and the effect of a high-fat meal on the bioavailability of that tablet--were investigated in a two-part, open, balanced crossover study in two panels of healthy subjects (12 per panel). Steady-state pharmacokinetics were investigated in an open-label study in which 24 healthy subjects were administered 120-mg single and multiple (once daily for 10 days) oral doses of etoricoxib tablets. The pharmacokinetics of etoricoxib were found to be consistent with linearity through doses at least twofold greater than the highest anticipated clinical dose of 120 mg. Etoricoxib administered as a tablet was rapidly and completely absorbed and available; the absolute bioavailability was estimated to be 100%. A high-fat meal decreased the rate of absorption without affecting the extent of absorption of etoricoxib; therefore, etoricoxib can be dosed irrespective of food. Steady-state pharmacokinetics of etoricoxib, achieved following 7 days of once-daily dosing, were found to be reasonably predicted from single doses. The accumulation ratio averaged 2.1, and the corresponding accumulation t1/2 averaged 22 hours, supporting once-daily dosing. Etoricoxib was generally well tolerated.

Application of Absorption Modeling to Predict Bioequivalence Outcome of Two Batches of Etoricoxib Tablets

“…This is supported by the high absolute bioavailability of etoricoxib (∼100%) indicating no solubility limitations to absorption (17). Furthermore, in a previously published report, Okumu et al (16) has demonstrated that the dissolution of etoricoxib in the stomach is the determining factor for bioavailability by the use of carefully designed AUC area under curve, C max maximum concentration, % CV coefficient of variation in vitro studies to probe intestinal precipitation coupled with absorption modeling was provided.…”

“…Due to the lower solubility at the pH 4-7 range, etoricoxib is classified as a low-solubility compound. When dosed orally, etoricoxib is completely and rapidly absorbed, with an oral bioavailability of up to 100% (17). Hence, it is classified as a BCS class II molecule.…”

“…Additional simulations at 30-and 60-mg doses were conducted to further assess the robustness of the model. The predicted and observed data (17) are summarized in Table IV. As can be seen from these simulations and the % prediction errors, the model predicts the observed data with reasonable accuracy for all the clinical studies simulated here.…”

Oral voriconazole and miconazole oral gel produce comparable effects on the pharmacokinetics and pharmacodynamics of etoricoxib

“…Oral bioavailability of etoricoxib tablets is nearly 100% [1]. Despite its negligible first-pass metabolism, the elimination of etoricoxib is characterized by extensive metabolism, with less than 1% of an oral dose detected as unchanged drug in urine [2].…”

Determination of etoricoxib in human plasma using automated on-line solid-phase extraction coupled with LC-APCI/MS/MS

“…[1][2][3] Etoricoxib is well orally absorbed, and following 120 mg single daily dosage to fasted adults, the peak plasma concentration (geometric mean C max = 3600 ng/mL) was observed at approximately 1 h (t max ). [4][5][6] An analytical high performance liquid chromatography (HPLC) method with photochemical cyclisation and fluorescence detection for the quantitation of etoricoxib in human plasma and urine was published using a structural analogue as internal standard and offline solid-phase extraction (SPE). 7 A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with atmospheric pressure chemical ionization (APCI) was validated over the concentration range of 0.5-250 ng/mL for the determination of etoricoxib in human plasma with a stable isotope as internal standard, and the run time of 8 min.…”