Evaluation of Generic Methods to Predict Human Pharmacokinetics Using Physiologically Based Pharmacokinetic Model for Early Drug Discovery of Tyrosine Kinase Inhibitors

Background Requirements for predicting human pharmacokinetics in drug discovery are increasing. Developing different methods of human pharmacokinetic prediction will facilitate lead optimization, candidate nomination, and dosing regimens before clinical trials at various early drug discovery stages....

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Bibliographic Details
Published in:European journal of drug metabolism and pharmacokinetics 2019-02, Vol.44 (1), p.121-132
Main Authors: Ren, Hong-Can, Sai, Yang, Chen, Tao
Format: Article
Language:English
Subjects:
Biomedical and Life Sciences
Biomedicine
Human Physiology
Medical Biochemistry
Original Research Article
Pharmaceutical Sciences/Technology
Pharmacology/Toxicology
Pharmacy
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Summary:Background Requirements for predicting human pharmacokinetics in drug discovery are increasing. Developing different methods of human pharmacokinetic prediction will facilitate lead optimization, candidate nomination, and dosing regimens before clinical trials at various early drug discovery stages. Objectives To develop and validate generic methods of human pharmacokinetic prediction to meet the requirements in early drug discovery. Methods The physiologically based pharmacokinetic (PBPK) model implemented in Gastroplus™ was used for human pharmacokinetic predictions. The absorption, distribution, metabolism, and excretion properties of drugs in humans predicted from molecular structure and extrapolated from tested preclinical data were used as inputs in the PBPK model. The approaches were validated by comparison of the predicted pharmacokinetic parameters with actual pharmacokinetic parameters of 15 marketed small-molecule compounds approved by the US Food and Drug Administration. Based on the validation and reported approaches, we proposed a strategy for human pharmacokinetic prediction at different drug discovery stages. Results Obvious underestimation of exposure (
ISSN:0378-7966
2107-0180
DOI:10.1007/s13318-018-0496-4