Modelling and PBPK simulation in drug discovery.
Physiologically based pharmacokinetic (PBPK) models are composed of a series of differential equations and have been implemented in a number of commercial software packages. These models require species-specific and compound-specific input parameters and allow for the prediction of plasma and tissue concentration time profiles after intravenous and oral administration of compounds to animals and humans. PBPK models allow the early integration of a wide variety of preclinical data into a mechanistic quantitative framework. Use of PBPK models allows the experimenter to gain insights into the properties of a compound, helps to guide experimental efforts at the early stages of drug discovery, and enables the prediction of human plasma concentration time profiles with minimal (and in some cases no) animal data. In this review, the application and limitations of PBPK techniques in drug discovery are discussed. Specific reference is made to its utility (1) at the lead development stage for the prioritization of compounds for animal PK studies and (2) at the clinical candidate selection and "first in human" stages for the prediction of human PK.
Jones
Hannah M
HM
Pfizer Global R&D, Department of Pharmacokinetics, Dynamics and Metabolism, IPC 654, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK. hannah.jones@pfizer.com
Gardner
Iain B
IB
Watson
Kenny J
KJ
D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D003198:Computer Simulation; D055808:Drug Discovery; D006801:Humans; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008954:Models, Biological; D009994:Osmolar Concentration; D004364:Pharmaceutical Preparations / Q000097:blood; D010599:Pharmacokinetics; D051381:Rats; D012984:Software; D013045:Species Specificity; D014018:Tissue Distribution
D004364:Pharmaceutical Preparations