Population pharmacokinetic-pharmacodynamic modelling of S 15535, a 5-HT(1A) 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 32784 (1-(benzodioxan-5-yl) 4-(5-hydroxyindan-2-yl)piperazine), and buspirone as a reference, were studied in male Wistar rats using a behavioural model of anxiety by determining the reduction in the number of fear-induced ultrasonic 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 pharmacokinetics and pharmacokinetic-pharmacodynamic relationships were described using non-linear mixed effects modelling. The no-drug effect was constant and all compounds were active in the model, reducing ultrasonic vocalisations immediately after administration. The sigmoid E(max) model was used to describe the pharmacokinetic-pharmacodynamic relationships, with E(max) values of a 90% decrease in baseline ultrasonic vocalisations. Corrected for plasma protein binding, all compounds showed similar potency. The study shows that ultrasonic vocalisations can be considered a suitable endpoint for the anxiolytic effect when used in conjunction with non-linear mixed effects modelling to overcome the limited sampling and effect measurements.
Servier Research and Development Ltd, Fulmer Hall, Windmill Road, Fulmer, Slough, SL3 6HH, UK. pvis@pharsight.com
P
P
Vis
O
O
Della Pasqua
M
M
Kruk
D
D
Martin
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E
Mocaër
M
M
Danhof
R
R
Jochemsen
D000818:Animals; D014151:Anti-Anxiety Agents / Q000097:blood* / Q000494:pharmacology; D002065:Buspirone / Q000097:blood*; D008297:Male; D017711:Nonlinear Dynamics; D010879:Piperazines / Q000097:blood* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000097:blood*; D014828:Vocalization, Animal / Q000187:drug effects / Q000502:physiology
D014151:Anti-Anxiety Agents; D010879:Piperazines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; C079549:4-(benzodioxan-5-yl)-1-(indan-2-yl)piperazine; D002065:Buspirone