Dose Selection Based on Physiologically Based Pharmacokinetic (PBPK) Approaches
- PDF / 441,737 Bytes
- 11 Pages / 595.276 x 790.866 pts Page_size
- 64 Downloads / 200 Views
Review Article Theme: Translational Modeling and Dose Selection: From Preclinical to Humans Guest Editors: Peter Bonate and Jenny Chien
Dose Selection Based on Physiologically Based Pharmacokinetic (PBPK) Approaches Hannah M. Jones,1,3 Kapil Mayawala,1 and Patrick Poulin2
Received 4 June 2012; accepted 28 November 2012; published online 27 December 2012 Abstract. Physiologically based pharmacokinetic (PBPK) models are built using differential equations to describe the physiology/anatomy of different biological systems. Readily available in vitro and in vivo preclinical data can be incorporated into these models to not only estimate pharmacokinetic (PK) parameters and plasma concentration–time profiles, but also to gain mechanistic insight into compound properties. They provide a mechanistic framework to understand and extrapolate PK and dose across in vitro and in vivo systems and across different species, populations and disease states. Using small molecule and large molecule examples from the literature and our own company, we have shown how PBPK techniques can be utilised for human PK and dose prediction. Such approaches have the potential to increase efficiency, reduce the need for animal studies, replace clinical trials and increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however some limitations need to be addressed to realise its application and utility more broadly. KEY WORDS: absorption; clearance; distribution; dose prediction; physiologically based pharmacokinetic modelling.
INTRODUCTION Physiologically based pharmacokinetic (PBPK) models are tools that can be used to predict the pharmacokinetics (PK) and in combination with pharmacokinetic–pharmacodynamic (PKPD) models, predict the dose of new drug entities. These models are constructed using a series of differential equations that are parameterised using known physiology and represent a quantitative mechanistic framework by which the absorption, distribution, metabolism and excretion of new drugs can be explored. For this reason, they provide a useful starting point to understand and extrapolate PK and dose across in vitro and in vivo systems and across different species, populations and disease states. Early reports of PBPK modelling use in the pharmaceutical industry are available but the application has been limited due to the mathematical complexity of the models and the large amounts of in vivo animal tissue concentration data required (1,2). However advances in the prediction of key parameters particularly tissue distribution such as the tissue to plasma partition coefficients (Kp values) (3–6) from in vitro and in silico 1
Systems Modelling and Simulation Group, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide R&D, 35 Cambridgepark Drive, Cambridge, Massachusetts 02140, USA. 2 4009 Sylvia Daoust, Québec City, Québec, Canada G1X 0A6. 3 To whom correspondence should be addressed. (e-mail: Hannah.Jones@pfizer.com)
data h
Data Loading...
