Laveille, C., Frey, N., Lerebours, G., Resplandy, G. And Jochemsen, R
I.R.I.S Courbevoie, France
S 16257, under development for treatment in myocardial ischaemia, belongs to the new pharmaceutical class of specific bradycardic agents. Its bradycardic activity is due to a direct effect on the sinus node. For this pharmacological effect, heart rate during exercise was chosen as a surrogate marker. Preclinical and in vitro experiments have shown that S 18982 (N-demethyl metabolite) had also some pharmacological properties, but only experiments in man can provide the quantitative information necessary to assess the contribution of this metabolite to the overall activity of the drug. Therefore, using phase I data, a population analysis was performed in order to determine the drug/metabolite potency ratio after administration of the parent drug.
So far, the drug was administered orally to more than 100 healthy male volunteers, as single doses of 0.5 to 40 mg , or twice daily doses of 8 to 32 mg up to 7 days. Multiple blood samples were taken per subject in order to estimate the pharmacokinetics of S 16257 and S 18982. As only few exercise tests could be performed per day for each subject, the variability among the pharmacodynamic sampling times was increased prospectively, in order to get a good distribution of heart rates measurements during exercise over the dosing. S 16257 and S 18982 were simultaneously assayed in plasma by an analytical procedure involving liquid-solid extraction, followed by reversed-phase liquid chromatography with native fluorescence detection. The limit of quantitation was 0.5 ng/ml (from 1 ml of plasma) for both entities.
The evolution of the S 16257/S 18982 plasma concentrations ratios varied as a function of time, this condition is necessary to estimate the drug/metabolite potency ratio without metabolite administration. In order to overcome potential problems for analysis of pharmacokinetic data, in parallel of the pharmacokinetic modelling, a non-parametric approach was investigated. This method uses linear regression of pairs of concentration-time data in order to interpolate plasma concentrations for the times at which pharmacodynamic measurements are available. Similar pharmacokinetic results were obtained between the non-parametric and the parametric approach. Using link models combined with an agonist/partial agonist model, the evolution of heart rates during exercise function of time were satisfactory described after the NONMEM analysis. The results suggested that in vivo in man, the metabolite was more potent that the parent drug.
The relative simplicity of the interpolation of concentration data has served to reduce the complexity of the PK/PD analysis. Furthermore, based on the findings of the metabolite contribution to the overall activity, new animal studies were started to explore the pertinence of a future administration of the metabolite in man.
Reference: PAGE 6 () Abstr 661 [www.page-meeting.org/?abstract=661]
Poster: poster