BACKGROUND AND OBJECTIVES:Pitavastatin is a highly effective lipid-lowering drug (approved dose range 1-4 mg/day) with a distinctive metabolic pathway that has a low potential for drug interactions. The efficacy and safety of pitavastatin have been characterized in a broad clinical development programme conducted initially in Japanese patients. The objectives of the present study were to evaluate the pharmacokinetic bioequivalence of the European (EU) and Japanese (JP) formulations of pitavastatin 2 mg in healthy Japanese and Caucasian men, and to assess whether the bioavailability of each formulation was similar in the two ethnic groups. METHODS: In this open-label, single-dose, two-way crossover pharmacokinetic study, healthy men aged 18-45 years were randomized to receive: the JP formulation of pitavastatin 2 mg followed by the EU formulation; or the EU formulation of pitavastatin 2 mg followed by the JP formulation. The main outcome measures were maximum plasma concentration (C(max)), area under the plasma concentration-time curve (AUC) during a dosage interval (τ) [AUC(τ)] and AUC from time zero to infinity (AUC(∞)) for pitavastatin and its main (inactive) metabolite pitavastatin lactone. Plasma concentrations of pitavastatin and pitavastatin lactone were determined using a validated liquid chromatography-tandem mass spectrometry method. RESULTS:Forty-eight Caucasian and 12 Japanese men completed the study. Compared with the Japanese men, the Caucasian men were of greater mean body weight (76.1 vs 58.9 kg), height (180.8 vs 170.8 cm) and body mass index (23.2 vs 20.2 kg/m2). Geometric mean ratios (GMRs) of the pharmacokinetic parameters of pitavastatin demonstrated bioequivalence of the EU and JP formulations: GMRs and 90% confidence intervals (CIs) fell within the range 80-125% in Caucasian men and in Caucasian and Japanese groups combined for pitavastatin C(max) (combined analysis: GMR 103.1% [90% CI 96.0, 110.6]), AUC(τ) (GMR 99.6% [90% CI 95.5, 104.0]), and AUC(∞) (GMR 104.2% [90% CI 96.2, 112.8]). After adjusting for age and body weight in the pooled formulation analysis, bioequivalence between the Caucasian and Japanese groups was similarly demonstrated for pitavastatin C(max) (GMR 96.8% [90% CI 90.2, 103.8]), AUC(τ) (GMR 98.3% [90% CI 94.2, 102.7]) and AUC(∞) (GMR 85.9% [90% CI 81.1, 91.0]). CONCLUSION: The EU and JP formulations of pitavastatin showed pharmacokinetic bioequivalence, and there were no clinically relevant differences in exposure to pitavastatin between Caucasian and Japanese participants when differences in body weight were taken into account.
RCT Entities:
BACKGROUND AND OBJECTIVES:Pitavastatin is a highly effective lipid-lowering drug (approved dose range 1-4 mg/day) with a distinctive metabolic pathway that has a low potential for drug interactions. The efficacy and safety of pitavastatin have been characterized in a broad clinical development programme conducted initially in Japanese patients. The objectives of the present study were to evaluate the pharmacokinetic bioequivalence of the European (EU) and Japanese (JP) formulations of pitavastatin 2 mg in healthy Japanese and Caucasian men, and to assess whether the bioavailability of each formulation was similar in the two ethnic groups. METHODS: In this open-label, single-dose, two-way crossover pharmacokinetic study, healthy men aged 18-45 years were randomized to receive: the JP formulation of pitavastatin 2 mg followed by the EU formulation; or the EU formulation of pitavastatin 2 mg followed by the JP formulation. The main outcome measures were maximum plasma concentration (C(max)), area under the plasma concentration-time curve (AUC) during a dosage interval (τ) [AUC(τ)] and AUC from time zero to infinity (AUC(∞)) for pitavastatin and its main (inactive) metabolite pitavastatin lactone. Plasma concentrations of pitavastatin and pitavastatin lactone were determined using a validated liquid chromatography-tandem mass spectrometry method. RESULTS: Forty-eight Caucasian and 12 Japanese men completed the study. Compared with the Japanese men, the Caucasian men were of greater mean body weight (76.1 vs 58.9 kg), height (180.8 vs 170.8 cm) and body mass index (23.2 vs 20.2 kg/m2). Geometric mean ratios (GMRs) of the pharmacokinetic parameters of pitavastatin demonstrated bioequivalence of the EU and JP formulations: GMRs and 90% confidence intervals (CIs) fell within the range 80-125% in Caucasian men and in Caucasian and Japanese groups combined for pitavastatin C(max) (combined analysis: GMR 103.1% [90% CI 96.0, 110.6]), AUC(τ) (GMR 99.6% [90% CI 95.5, 104.0]), and AUC(∞) (GMR 104.2% [90% CI 96.2, 112.8]). After adjusting for age and body weight in the pooled formulation analysis, bioequivalence between the Caucasian and Japanese groups was similarly demonstrated for pitavastatin C(max) (GMR 96.8% [90% CI 90.2, 103.8]), AUC(τ) (GMR 98.3% [90% CI 94.2, 102.7]) and AUC(∞) (GMR 85.9% [90% CI 81.1, 91.0]). CONCLUSION: The EU and JP formulations of pitavastatin showed pharmacokinetic bioequivalence, and there were no clinically relevant differences in exposure to pitavastatin between Caucasian and Japanese participants when differences in body weight were taken into account.
Authors: Thorir D Bjornsson; John A Wagner; Stephen R Donahue; Dawn Harper; Aziz Karim; Marlene S Khouri; William R Murphy; Kristin Roman; Dennis Schneck; Daryl S Sonnichsen; Dennis J Stalker; Stephen D Wise; Stuart Dombey; Caroline Loew Journal: J Clin Pharmacol Date: 2003-09 Impact factor: 3.126