健康成人被験者で高含量の向精神薬の生物学的同等性試験を行うことの妥当性:―クエチアピンおよびプラミペキソールでの検討―

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The aims of the present study were (1) to determine the maximum tolerated doses of quetiapine and pramipexole when given to healthy Japanese male subjects using gradually increasing single doses; (2) to evaluate the feasibility of this exploratory method for further bioequivalence trials; and (3) to conduct bioequivalence trials using doses determined based on prior tolerability trials. For quetiapine, 18 participants received 25 mg in the first stage. In the second stage, participants were divided into three groups of six subjects each and allocated to receive 50 mg, 75 mg or 100 mg depending on the severity of adverse events in the first stage. For pramipexole, 18 participants received 0.125 mg in the first stage, and then received 0.25 mg, 0.375 mg, or 0.5 mg in the second stage in the same manner as quetiapine. In the group receiving 75 mg of quetiapine, three mild adverse events and seven moderate adverse events (including nightmare and syncope) were reported from all six subjects. In the group receiving 0.5 mg of pramipexole, three mild and five moderate adverse events were reported from five subjects. Therefore, we judged that doses equal to or greater than 75 mg of quetiapine and 0.5 mg of pramipexole are not well tolerated by healthy subjects. Based on these results, we conducted two-way crossover bioequivalence clinical trials with brand-name and generic formulations of 25 mg of quetiapine (25 mg tablets or 50% fine granules) and 0.125 mg of pramipexole, in subjects who did not participate in the tolerability studies. By calculating 90% confidence intervals of logarithmic transformed values of Cmax and AUCt, we found that the brand-name and generic formulations were bioequivalent.

健康成人被験者で高含量の向精神薬の生物学的同等性試験を行うことの妥当性:―クエチアピンおよびプラミペキソールでの検討―

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