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Physiologically-Based Pharmacokinetic Modeling in Lead Optimization I: Evaluation and Adaptation of GastroPlus® to Predict Bioavailability of Medchem Series

Martin, Eric and Daga, Pankaj and Bolger, Michael and Haworth, Ian and Clark, Robert (2018) Physiologically-Based Pharmacokinetic Modeling in Lead Optimization I: Evaluation and Adaptation of GastroPlus® to Predict Bioavailability of Medchem Series. Molecular Pharmaceutics. ISSN 1543-83841543-8392

Abstract

When medicinal chemists need to improve bioavailability (%F) within a chemical series during lead optimization, they synthesize new series members with systematically modify 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 have poor performance and projects have too little data to train local %F QSPR models. Physiologically-based pharmacokinetics (PBPK) models simulate the movement of a drug through an animal. Usually, PBPK simulations are carefully tuned for a few advanced drug candidates, using a combination of in vitro, in vivo and calculated inputs, to estimate human doses for clinical trials, or to prioritize compounds for expensive animal studies. 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.

Item Type: Article
Keywords: physiologically-based pharmacokinetics, PBPK, oral bioavailability, %F, lead optimization
Date Deposited: 06 Mar 2018 00:45
Last Modified: 06 Mar 2018 00:45
URI: https://oak.novartis.com/id/eprint/35090

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