PURPOSE: 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. MATERIALS AND 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.
PURPOSE: 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. MATERIALS AND 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.
Authors: Klaas P Zuideveld; Piet H Van der Graaf; Donald Newgreen; Richard Thurlow; Nicola Petty; Paul Jordan; Lambertus A Peletier; Meindert Danhof Journal: J Pharmacol Exp Ther Date: 2004-01-08 Impact factor: 4.030
Authors: Klaas P Zuideveld; Jasna Rusiç-Pavletiç; Hugo J Maas; Lambertus A Peletier; Piet H Van der Graaf; Meindert Danhof Journal: J Pharmacol Exp Ther Date: 2002-12 Impact factor: 4.030
Authors: Martin Johnson; Magdalena Kozielska; Venkatesh Pilla Reddy; An Vermeulen; Cheryl Li; Sarah Grimwood; Rik de Greef; Geny M M Groothuis; Meindert Danhof; Johannes H Proost Journal: Pharm Res Date: 2011-06-07 Impact factor: 4.200
Authors: Martin Johnson; Magdalena Kozielska; Venkatesh Pilla Reddy; An Vermeulen; Hugh A Barton; Sarah Grimwood; Rik de Greef; Geny M M Groothuis; Meindert Danhof; Johannes H Proost Journal: Pharm Res Date: 2014-05-03 Impact factor: 4.200