Stephen Duffull(1), Leon Aarons(1) and the THERMOS group(2).
1. School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK.; 2. THERapeutic MOdelling and Simulation group: SPC Lyon, France; IRIS, Servier, Courbevoie, France; Dept of Applied Mathematics and Informatics, University of Ghent, Belgium; School of Pharmacy and Pharmaceutical Sciences, University of Manchester, UK.
Ivabradine is a novel bradycardiac agent that has been developed for the treatment of angina and tachyarrhythmias. Ivabradine has an active metabolite S-18982. The pharmacokinetics and effect on heart rate have been reported previously for group of 18 healthy volunteers. The aim of this study was to develop a linked pharmacokinetic-pharmacodynamic simulation model.
The pharmacokinetic data and pharmacodynamic data (heart rate) were pooled from two studies and included a total of 78 healthy subjects. Eighteen of these subjects were reported previously (Ragueneau et al. Clin Pharmacol Ther 1998;64:192-203). The data consisted of single dose intravenous and multiple dose oral administration of ivabradine. The multiple dose regimens were administered every 12 hours. There were 9 active dosing levels a placebo dose and a no-dose run in period before each study. The modelling was performed using NONMEM software.
The pharmacokinetics of ivabradine and S-18982 were best described by a linked 2 compartment, for both ivabradine and S-18982, intravenous bolus and first order input and output model. Both ivabradine and S-18982 appeared to possess bradycardic activity although the extent of the activity of each could not be determined from the data available. A multiple ligand pharmacodynamic model provided the best fit to the data, where Emax was set as the same value for both ivabradine and S-18982 and the EC50 of S-18982 was set at 1.2 times the value for ivabradine (from in vitro data). No time-effect trend was seen in the pre-treatment effects or placebo dose on heart rate.
A linked pharmacokinetic-pharmacodynamic model for description of the time course of effect of ivabradine, and metabolite S-18982, has been developed. All models were assessed in terms of their posterior predictive performance and were able to describe the original data adequately when used for simulation purposes. It was not possible to determine the differential effects of ivabradine and its metabolite in terms of heart rate. The model was considered suitable for use for simulation purposes.
Supported by grant BIOMED PL 962640 from E.C.
Reference: PAGE 8 () Abstr 76 [www.page-meeting.org/?abstract=76]
Poster: oral presentation