A pharmacokinetic simulation model for ivabradine in healthy volunteers

Ivabradine is a novel bradycardic agent that has been developed for the pre vention of angina. Ivabradine has an active metabolite S-18982. The aim of this study is to develop a pharmacokinetic simulation model. Pharmacokineti c data from two studies were pooled and included data from a total of 66 he althy male volunteers. The data were collected following single dose intrav enous and multiple dose oral administration of ivabradine. The multiple dos e regimens were administered every 12 h and there were seven active dosing levels. The modelling was performed using the NONMEM software. The model wa s assessed in terms of its ability to describe the original data set used i n its construction and also data arising from a different clinical pharmaco logy study involving 12 additional subjects. The pharmacokinetics of ivabra dine and S-18982 were best described by two linked two compartment intraven ous bolus and first-order input, with first-pass loss, and first-order outp ut model. When the model was used for simulation it produced an adequate de scription of both the original data and data arising from a different clini cal pharmacology study. (C) 2000 Elsevier Science B.V. All rights reserved.