Laveille C. a), Le Coz F. b), Lerebours G. a), Resplandy G. a), and Jochemsen R. a)
a) I.R.I.S., 6 Place des Pleiades, F-92415 Courbevoie Cedex, France b) BIOTRIAL, Technopole Atalante Villejean, 35000 Rennes, France
S-16257 is a bradycardic agent potentially developed for the treatment of myocardial ischaemia. It belongs to the class of specific bradycardic agents or sino-atrial modulators. Therefore heart rate during exercise test was used as a surrogate marker. In order to investigate the relationship between S-16257 plasma concentrations and heart rate during exercise, a population approach was performed, because only sparse pharmacodynamic data could be obtained. The first step was to characterise the S-16257 pharmacokinetics.
Two phase I studies were performed in order to describe the S-16257 pharmacokinetics after repeated administration. During these two studies, S-16257 was administered on a twice daily dosage regimen and blood samples were drawn after the morning dose. Results (Cmin) suggested that the pharmacokinetic profile of S-16257 was different when the drug was administered in the morning, under fasting conditions, and in the evening, just after dinner.
Therefore, a new study was initiated in order to determine the influence of food on the pharmacokinetics of S-16257 administered as a single oral dose and also the inter and intraindividual variabilities in S-16257 pharmacokinetics at steady-state following a repeated oral administration. This phase I study was a single centre, 2-period, randomised, cross-over open study. For each of the 12 healthy volunteers, each period consisted of a single oral administration of S-16257, either fasting or a the end of a standard meal, followed by a 4-day bid repeated administration. A full pharmacokinetic screen was performed after each single administration (12 blood samples), contrary to the repeated regimen where few blood samples (4 blood samples) were drawn after the morning and the evening dose, respectively.
A population approach was performed with the NONMEM software in order to study:
– intra and interindividual variabilities,
– influence of covariate like food and time of administration.
Results of this study will presented in June 1996 at Canterbury.
Reference: PAGE 5 (1996) Abstr 557 [www.page-meeting.org/?abstract=557]
Poster: poster