Development of a sequential linked pharmacokinetic and pharmacodynamic simulation model for ivabradine in healthy volunteers

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Abstract

Ivabradine is a novel bradycardic agent that has been developed for the prevention of angina. Ivabradine has an active metabolite S-18982. The aim of the study was to develop a linked pharmacokinetic–pharmacodynamic simulation model for the description of exercise-induced heart rate. The pharmacodynamic data (heart rate) were pooled from two studies and included a total of 78 healthy subjects. The data consisted of multiple dose oral administration of ivabradine. The multiple dose regimens were administered every 12 h. There were eight active dosing levels and placebo, and a no-dose run in the period before each study. The modelling was performed using the NONMEM software. Both ivabradine and S-18982 possess bradycardic activity, although the extent of the activity of both could not be determined from the data available. A multiple ligand pharmacodynamic model provided the best fit to the data. The model was assessed in terms of its posterior predictive performance and was able to describe the original data adequately when used for simulation purposes.

Introduction

Ivabradine is a novel bradycardic agent that has been developed for the prevention of angina and myocardial ischaemia. It acts by reducing the slope of the slow diastolic depolarisation in the automatic cells of the sinoatrial node by inhibiting the if pacemaker current. It is considered to have no effect on cardiac contractility in terms of positive or negative inotropic effects. The N-dealkylated metabolite, S-18982, has also been shown to decrease heart rate in pre-clinical studies when administered to dogs (Ragueneau et al., 1998). There are no reports of the administration of S-18982 in humans.

The pharmacokinetics and pharmacodynamics of ivabradine have been reported previously (Ragueneau et al., 1998, Duffull et al., 2000). In the former report the pharmacokinetics and pharmacodynamics were studied from a group of 18 subjects who received both oral and intravenous dosing. The pharmacodynamic endpoint was exercise-induced heart rate. The pharmacokinetic analyses were linked to heart rate by way of a hypothetical effect compartment. The different routes of administration and the effects of parent and metabolite were modelled separately. The current analysis incorporates these 18 subjects with an additional 60 subjects from another study and considers the relationship between the pharmacokinetics of ivabradine and S-18982 and heart rate in a combined model. The relationship between dose and concentration for ivabradine and S-18982 was developed previously from the same two studies (Duffull et al., 2000).

The aim of this analysis was to develop a simulation model that describes the pharmacokinetic–pharmacodynamic relationships of ivabradine and its metabolite S-18982.

Section snippets

Subjects

Seventy-eight healthy male volunteers were included in this analysis. These subjects arise from two studies.

The first study of 18 subjects was reported by Ragueneau et al. (1998) and is described only briefly here. The subjects received no medication for 3 weeks prior to commencing the study. They were then randomised to receive either 10 or 20 mg of ivabradine in a parallel design with nine subjects in each arm. Ivabradine was administered orally on day 1 and then starting at 24 h after this

Results

The preliminary model building analysis, where the observed concentration was naively assumed to be the expected concentration, identified both the general parametric model for non-additivity (Eq. (4)) and the multiple ligand model (Eq. (5)) as possible models. A summary of the preliminary modelling is presented in Table 1. We then performed a full linked sequential pharmacokinetic/pharmacodynamic analysis for both models with the addition of a hypothetical effect compartment. The general

Discussion

A sequential linked pharmacokinetic–pharmacodynamic analysis is reported for ivabradine and its active metabolite S-18982. This analysis is similar in part to that performed previously by Ragueneau et al. (1998), although all of the pharmacokinetic models were combined into a single model prior to undertaking the pharmacodynamic analysis and the pharmacodynamic models for ivabradine and S-18982 were combined using a multiple ligand model. In contrast to the previous analysis we were unable to

Acknowledgements

Supported by grant BIOMED PL 962640 from the European Community. The authors would like to acknowledge the help and advice of the members of the THERMOS (THERapeutic MOdelling and Simulation) group.

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