Allometric scaling of pharmacodynamic responses: application to 5-Ht1A receptor mediated responses from rat to man.
OBJECTIVE
The aim of the present study was to assess whether two widely used biomarkers for 5-HT(1A)-receptor mediated responses in the rat (hypothermia and corticosterone increase) could be scaled to man using allometric principles.


METHODS
Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) models were developed and characterized in rats for the standard 5-HT(1A)-receptor agonists, buspirone and flesinoxan. Allometric scaling was investigated on the basis of simulation taking into account the inter-individual variability and clinical study design. The model-predicted effects of both flesinoxan and buspirone were compared to those published in the literature.


RESULTS
The main finding of this analysis was that for both hypothermia and cortisol increase, the model could predict the extent of the pharmacological response in man adequately. For the hypothermic response, the time course of the response was also predicted with a high degree of accuracy. In contrast, in the case of the cortisol response, the observed time lag was, despite the fact that it fell within the model uncertainty, not predicted.


CONCLUSIONS
Based on these analyses, it is concluded that allometrically scaled mechanism based PK-PD models are promising as a means of predicting the pharmacodynamic responses in man. This approach provides for a novel way of interpreting and scaling pre-clinical pharmacological responses and ultimately facilitates the understanding and prediction of pharmacological responses in man.
Zuideveld
Klaas P
KP
Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratory, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.
Van der Graaf
Piet H
PH
Peletier
Lambertus A
LA
Danhof
Meindert
M
D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D002065:Buspirone / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*
D010879:Piperazines; D044282:Receptor, Serotonin, 5-HT1A; C056895:flesinoxan; D002065:Buspirone; D006854:Hydrocortisone