Physiologically Based Pharmacokinetic Modeling in Lead Optimization. 1. Evaluation and Adaptation of GastroPlus To Predict Bioavailability of Medchem Series.
Mol Pharm
; 15(3): 821-830, 2018 03 05.
Article
em En
| MEDLINE
| ID: mdl-29337578
ABSTRACT
When medicinal chemists need to improve bioavailability (%F) within a chemical series during lead optimization, they synthesize new series members with systematically modified properties mainly by following experience and general rules of thumb. More quantitative models that predict %F of proposed compounds from chemical structure alone have proven elusive. Global empirical %F quantitative structure-property (QSPR) models perform poorly, and projects have too little data to train local %F QSPR models. Mechanistic oral absorption and physiologically based pharmacokinetic (PBPK) models simulate the dissolution, absorption, systemic distribution, and clearance of a drug in preclinical species and humans. Attempts to build global PBPK models based purely on calculated inputs have not achieved the <2-fold average error needed to guide lead optimization. In this work, local GastroPlus PBPK models are instead customized for individual medchem series. The key innovation was building a local QSPR for a numerically fitted effective intrinsic clearance (CLloc). All inputs are subsequently computed from structure alone, so the models can be applied in advance of synthesis. Training CLloc on the first 15-18 rat %F measurements gave adequate predictions, with clear improvements up to about 30 measurements, and incremental improvements beyond that.
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MEDLINE
Assunto principal:
Química Farmacêutica
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Relação Quantitativa Estrutura-Atividade
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Inibidores Enzimáticos
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Descoberta de Drogas
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Modelos Biológicos
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article