22 Population Pharmacokinetic-Pharmacodynamic of a New Specific Bradycardic Agent: S-16257

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.