V. Cosson, R. Jochemsen, M. Dubar, J.M. Delbos, H. Merdjan.
Background: S 18326 is a potent and selective direct thrombin inhibitor proposed as anti-thrombotic agent. S 18326 has been administered so far intravenously and orally (solution) during phase I studies.
Aim: To design oral dosing formulation to reach the desired pharmacodynamic effects as defined by the clinicians within the therapeutic limitations required by the safety: the pharmacodynamic endpoint maintained above 1.3 for pharmacologic efficacy and under 3 for safety.
Methods: The pharmacokinetic and the pharmacokinetic/pharmacodynamic models were determined using NONMEM based on data from 42 healthy male volunteers who received S 18326 in the phase I intravenous increasing dose study and from 14 male volunteers who received S 18326 in the phase I oral increasing dose study. The pharmacodynamic endpoint was the relative activated partial thromboplastin (aPTT) time considered as the reference test to monitor the anticoagulant effect. Using the defined population pharmacokinetic and pharmacokinetic /pharmacodynamic models a series of pharmacokinetic and pharmacodynamic profiles of hypothetical oral formulations (different release of drug) were simulated according to different administration schemes (1, 2 or 3 administrations per days) at doses of 50, 100 and 150 mg.
Results: The pharmacokinetics of intravenous S 18326 was described by a 2 compartment model parameterised in clearances and volumes.
A direct correlation of S 18326 plasma level and relative aPTT was observed after intravenous dosing or oral solution. The population pharmacokinetic-pharmacodynamic relationship identified was a logarithmic relationship.
The relative aPTTmax observed after the administration of a 60 mg solution of S 18326 was equal to 2.01. The simulations have shown that the administration of the hypothetical oral formulations of S 18326 with a 4 hour absorption duration, at 100 mg yielded a aPTTmax of 1.97 at the first peak and of 2.02 at the second peak and fitted the therapeutic limitations.
Discussion/Conclusion: A zero order absorption lasting 4 hours should ensure a better duration of the therapeutic efficacy for the subjects while avoiding an haemorrhagic risk linked to a peak-effect, and consequently should also allow the administration of higher doses with less risk. Based on these simulation results, the biopharmaceutic department had a clear idea of the type of oral formulation to elaborate for targeting the desired pharmacodynamic effect.
Reference: PAGE 8 (1999) Abstr 145 [www.page-meeting.org/?abstract=145]
Poster: poster