Applications of physiologically based absorption models in drug discovery and development

被引:95
|
作者
Parrott, Neil [1 ]
Lave, Thierry [1 ]
机构
[1] F Hoffmann La Roche & Co Ltd, Drug Metab & Pharmacokinet Dept, Modeling & Simulat Grp,Pharmaceut Div, Pharma Res Non Clin Dev,Non Clin Drug Safety, CH-4002 Basel, Switzerland
关键词
modeling and simulation; pharmacokinetics; physiologically based pharmacokinetic (PBPK); absorption model; advanced compartmental and transit (ACAT); GastroPlus;
D O I
10.1021/mp8000155
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
This article describes the use of physiologically based models of intestinal drug absorption to guide the research and development of new drugs. Applications range from lead optimization in the drug discovery phase through clinical candidate selection and extrapolation to human to phase 2 formulation development. Early simulations in preclinical species integrate multiple screening data and add value by transforming these individual properties into a prediction of in vivo absorption. Comparison of simulations to plasma levels measured after oral dosing in animals highlights unexpected behavior, and parameter sensitivity analysis can explore the impact of uncertainties in key properties, point toward factors which are limiting absorption and contribute to assessment of compound developability. Physiological models provide reliable prediction of human absorption and with refinement based on phase 1 data are useful guides to further market formulation development. Improvements in the accuracy of simulations are expected as better in vitro methods generate more in vivo relevant solubility and permeability data, and modeling will play a central role in the development of more predictive methods for transporter-related effects on drug absorption.
引用
收藏
页码:760 / 775
页数:16
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