Population pharmacokinetic-pharmacodynamic modelling of S 15535, a 5-MT1A receptor agonist, using a behavioural model in rats

The pharmacokinetic-pharmacodynamic relationship of S 15535 (1-(benzodioxan -5-yl) 4-(indan-2-yl)piperazine) and its active 5-hydroxy metabolite S 3278 4 (1-(benzodioxan-5-yl) 4-(5-hydroxyindan-2-yl)piperazine). and buspirone a s a reference, were studied in male Wistar rats using a behavioural model o f anxiety by determining the reduction in the number of fear-induced ultras onic vocalisations. S 15535 and buspirone were administered p.o. and i.v. S 32784. present in man but not in rat, was administered i.v. The pharmacoki netics and pharmacokinetic-pharmacodynamic relationships were described usi ng non-linear mixed effects modelling. The no-drug effect was constant and all compounds were active in the model, reducing ultrasonic vocalisations i mmediately after administration. The sigmoid E-max model was used to descri be the pharmacokinetic-pharmacodynamic relationships, with E-max values of a 90% decrease in baseline ultrasonic vocalisations. Corrected for plasma p rotein binding, all compounds showed similar potency. The study shows that ultrasonic vocalisations can be considered a suitable endpoint for the anxi olytic effect when used in conjunction with non-linear mixed effects modell ing to overcome the limited sampling and effect measurements. (C) 2001 Publ ished by Elsevier Science B.V.