Jerome T. Mettetal, Mark Pinches, Teresa Collins, Karin Skansen, Paul Morgan
Translational Safety, Drug Safety and Metabolism, AstraZeneca
Objectives: Safety margin assessments due to PPAR-gamma activity in toxicological studies is often confounded by study length and species sensitivity [1]. Here we attempt to increase the interpretability of these studies by comparing the TK/TD relationships of known PPAR-gamma agonists between dog, a key toxicological species, and man.
Methods: To assess the effects of PPAR-gamma agonist activity on the cardiovascular system we examined hematocrit and haemoglobin, markers of plasma volume expansion [2], under chronic dosing in dog and man for rosiglitazone and tesaglitazar, both potent PPAR-gamma agonists. Models describing the time-course of hematocrit and haemoglobin reduction were then established in both species.
Results: Indirect response models with linear dose-dependent inhibition on production were used to describe the time-course of plasma volume expansion, based on hematocrit and haemoglobin reduction, during both treatment and recovery. The parameter determining the timescale of haematological effect was broadly comparable across compounds and species reflecting slow changes to haematological endpoints. The sensitivity to drug was likewise assessed and differences compared between species and compounds.
Conclusions: The models developed provide a mechanism for interpretation of preclinical toxicological findings by increasing translatability of findings between studies of different duration as well as between species.
References:
[1] J. El-Hage, Peroxisome Peroxisome Proliferator-Activated Proliferator-Activated Receptor (PPAR) Agonists Preclinical and Clinical Cardiac Safety Considerations, FDA Presentation
[2] C. Nofziger and B. Blazer-Yost, J Am Soc Nephrol 20: 2481–2489, 2009
Reference: PAGE 23 (2014) Abstr 3234 [www.page-meeting.org/?abstract=3234]
Poster: Drug/Disease modeling - Safety