臨床薬理

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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 C_max (ng/mL) of paroxetine was 0.78 in ultra-rapid metabolizers (UM; n=1), 5.82 in extensive metabolizers (EM; n=24), and, 18.60 in intermediate metabolizers (IM; n=4). Mean AUC _t (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.

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Some controversial issues concerning pediatric clinical trials exist in Japan. The aim of this study was to investigate the psychological issues specific to pediatric clinical trials. We encounter difficulties in the clinical setting when conducting pediatric trials in Japan, because of the well established universal health insurance system with a strong focus on patient benefit and the close relationship between parents and children which is common among Asian people. In order to define the specific pediatric issues, we conducted a study on the psychology of parents whose children had participated in clinical trials of antibacterial antibiotics for acute otitis media or anti-allergic agents. In this study, a questionnaire survey was conducted on 51 parents of 61 pediatric trial participants. Twenty-five parents (49%) responded to the questionnaire at the completion of clinical trial. From the responses, we attempted to identify important issues that have to be resolved. The results indicated several unique and deep psychological issues in the parents. Some parents felt a sense of guilt for receiving a stipend as a result of their children's participation in the trials. During the trials, parents tended to hide their vague anxieties over their children's physical conditions from the investigators and the clinic staff. We will conduct further analysis to identify the most critical psychological factor, the solution of which will facilitate successful implementation of clinical trials involving children in the future.

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