C. Laveille, N. Frey, G. Lerebours, G. Resplandy, Jochemsen, R.
Institut de Recherches Internationales Servier, 6 place des Pleiades, 92415 Courbevoie, Cedex, (France)
S-16257 belongs to the new pharmaceutical class of specific bradycardic agents. Its bradycardic activity is due to a direct effect on the sinus mode. For this pharmacological effect, heart rate during exercise was used as a surrogate marker. This compound is under development for treatement in myocardial ischaemia.
Two phase I studies have been made :
- increasing single oral dose (placebo, 2, 4, 8, 16, 24, 32 and 40 mg) with 60 subjects, generating 540 plasma concentrations.
- increasing repeated oral dose during seven days (placebo, 8,16, 20, 24, 28 and 32 mg twice a day) with 60 subjects, generating 1056 plasma concentrations.
Bicycle tests with an increasing workload have been made and heart rate was measured during these exercises :
- in the single oral dose study :
- before administration,
- 2, 6, 10 and 24 hours after administation.
- in the repeated oral dose study :
- the first day, before administration, 2 and 10 hours after administration,
- the fourth day, 1 and 10 hours after administration,
- the seventh day, 4, 10 and 24 hours after the last administration.
The objectives for these two studies were :
- to observe the safety and tolerance of S-16257,
- to investigate the relationship between plasma concentration of S-16257 and heart rate during exercise.
In order to analyse the sparse pharmacodynamic data a population approach was performed with the NONMEM program :
- pharmacokinetic model : two-compartment open model with first-order input
- link model : effect compartment
- pharmacodynamic model : sigmoid Emax model
The preliminary results seem to show some differences between single and repeated oral dose.
Completed analysis will be presented in June 1995.
Reference: PAGE 4 (1995) Abstr 625 [www.page-meeting.org/?abstract=625]
Poster: oral presentation