Investigation of bioequivalence between MSG203 and Paxil® (paroxetine hydrochloride hydrate) after single oral administration in Japanese healthy male subjects: Detailed study in different CYP2D6 phenotypes

Abstract

MSG203 was developed by Meiji Seika Pharma Co., Ltd. as a generic drug of paroxetine hydrochloride hydrate (Paxil® Tablets). Paroxetine is mainly metabolized by CYP2D6. Therefore, in addition to the evaluation of bioequivalence between MSG203 and Paxil®, the effects of CYP2D6 polymorphism on the pharmacokinetic (PK) parameters of plasma paroxetine were also investigated. Ninety-six Japanese healthy subjects aged 20-35 years participated in the study. The study was performed in 3 different groups : MSG5 group compared 2 tablets of MSG203 5 mg versus 1 tablet of Paxil® 10 mg : MSG10 group compared 1 tablet of MSG203 10 mg versus 1 tablet of Paxil® 10 mg ; and MSG20 group compared 1 tablet of MSG203 20 mg versus 1 tablet of Paxil® 20 mg. Bioequivalence between MSG203 and Paxil® was confirmed in all three groups. The safety profiles of both drugs were also similar. The PK parameters after a single oral dose of MSG203 20 mg in subjects with different CYP2D6 phenotypes were as follows. Mean Cmax (ng/mL) of paroxetine was 0.78 in ultra-rapid metabolizers (UM : n = l), 5.82 in extensive metabolizers (EM : n = 24), and, 18.60 in intermediate metabolizers (IM : n = 4). Mean AUC, (ng·h/mL) was 7.93 in UM, 88.52 in EM, and 495.61 in IM. Similar PK profiles in these phenotypes were confirmed after a single oral dose of Paxil®. In this study, plasma concentrations of paroxetine were very low because of the high clearance profile in UM subjects. Generally, inadequate treatment would occur in patients with the UM phenotype of CYPs. However, information on the PK profiles in different CYP phenotypes is insufficient. Evaluation of the PK profiles of drugs in different CYP phenotypes provides valuable information for clinical use of drugs that are metabolized by polymorphic enzymes.