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薬理と治療
- Authors: Kumiko Miyata1, 他
Abstract
Background Eldecalcitol, which was developed by Chugai Pharmaceutical Co., Ltd.(Tokyo,Japan)as a treatment for osteoporosis, is a new derivative of active vitamin D3 (1,25(OH)2D3)with a hydroxypropyloxy group introduced at the 2β position. Vitamin D has been reported toinduce CYP3A4 in the gastrointestinal tract in in vitro studies1,2). It is important to investigatethe effects of eldecalcitol on CYP3A4 because many medicinal products are substrates ofCYP3A4, and it is very likely that some will be used concomitantly by patients takingeldecalcitol.Objectives The objectives of this study were to determine the effects of multiple doses ofeldecalcitol on the drug-metabolizing enzyme, CYP3A4, and to verify safety in healthy malevolunteers.Methods To investigate the effects of eldecalcitol on the drug-metabolizing enzyme,CYP3A4, double-blinded eldecalcitol 0.75 μg or placebo was orally administered once dailyfor 14 days in healthy male volunteers, and a probe drug(simvastatin), which is a substrateof CYP3A4, was orally administered on the day before the start and the day after completionof dosing of eldecalcitol. The effects of eldecalcitol on the drugmetabolizing enzyme,CYP3A4, were investigated by comparing the pharmacokinetics of simvastatin and its metabolite,simvastatin hydroxyacid, at baseline and after multiple doses of eldecalcitol.Results The geometric mean ratios of the Cmax and AUClast for simvastatin were 1.158 and0.964, respectively, in the placebo group and 0.809 and 0.848, respectively, in the eldecalcitolgroup. The geometric mean ratios of the Cmax and AUClast for the metabolite, simvastatinhydroxyacid, were 0.958 and 0.874, respectively, in the placebo group and 0.894 and 0.929,respectively, in the eldecalcitol group. The 90 % confidence intervals for these parameterswere all inclusive of 1 other than the Cmax for simvastatin in the eldecalcitol group. The Cmaxof simvastatin showed a tendency to decrease after multiple doses of eldecalcitol, but theAUClast of simvastatin and the Cmax and AUClast of the open-acid form were unchanged, andtherefore the effects on CYP3A4 of multiple doses of eldecalcitol were not considered to beclinically relevant.Conclusions The effects of multiple doses of eldecalcitol on CYP3A4 were not consideredto be clinically relevant. There were no adverse events considered to be clinically significant,and there were no variations seen in laboratory test or physiological test values and 12-leadECG. From pharmacokinetic and safety standpoints, it is unlikely that there were clinicallyrelevant even if patients were to take eldecalcitol for long periods and concomitantly take oneof the many medicinal products that are substrates of CYP3A4.(Jpn Pharmacol Ther 2011;39:275-85)
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