Use of PBPK modelling in drug discovery at Pfizer
Hannah M Jones
Pfizer PGRD, Sandwich, UK
Objectives: Physiologically-based pharmacokinetic (PBPK) models are composed of a series of differential equations and have been implemented in a number of commercial software packages. Integration of species and compound specific data into these models allow for the prediction of plasma and tissue concentration time profiles after intravenous and oral administration of compounds to animals and humans. The aim of this work was to prospectively explore the utility of such models in a drug discovery setting.
Methods: The PBPK strategy proposed by Jones et al., 2006 and validated by De Buck et al., 2007 was followed in all cases. The following applications were investigated: 1. simulation of human PK; 2. simulation of food effects in human and 3. simulation of high dose preclinical TK exposure.
Results: In the majority of cases, the PBPK models (as implemented in GastroPlusTM) together with the relevant input data were able to accurately predict the PK of the compounds studied in the presence and absence of food. Prediction accuracy tended to decrease with increasing dose as a result of saturable clearance mechanisms that were not incorporated into the model.
Conclusions: PBPK models were used to enable the early integration of a wide variety of preclinical data into a mechanistic quantitative framework, allowing the scientist to gain insights into the properties of a compound, ultimately guiding experimental efforts and enabling effective design of clinical studies.
References:
[1] H.M. Jones, N. Parrott, K. Jorga and T. Lave. A novel strategy for physiologically based predictions of human pharmacokinetics. Clin Pharmacokinet 45(5): 511-42 (2006).
[2] S.S. De Buck, V.K. Sinha, L.A. Fenu, M.J. Nijsen, C.E. Mackie and R.A.H.J. Gilissen. Prediction of human pharmacokinetics using physiologically based modeling: A retrospective analysis of 26 clinically tested drugs. Drug Metab Dispos 35(10): 1766-80 (2007).