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Evaluation of the Gastroplus Advanced Compartmental and Transit (ACAT) Model in Early Discovery

Gobeau, Nathalie and Stringer, Rowan and De Buck, Stefan and Tuntland, Tove and Faller, Bernard (2016) Evaluation of the Gastroplus Advanced Compartmental and Transit (ACAT) Model in Early Discovery. Pharmaceutical Research, 33 (9). pp. 2126-2139. ISSN 0724-8741

Abstract

Purpose. The aim of this study was to evaluate the oral exposure predictions obtained early in drug discovery with a generic Gastroplus Advanced Compartmental And Transit (ACAT) model based on the in vivo intravenous blood concentration-time profile, in silico properties (lipophilicity, pKa) and in vitro high-throughput absorption-distribution-metabolism-excretion (ADME) data (Parallel Artificial Membrane Permeability Assay, solubility, liver microsomal stability) .
Methods. The generic Gastroplus ACAT model is based on a series of basic assumptions, such as the hepatic clearance being mainly mediated by cytochrome P450 enzymes, combined with in silico predictions, high throughput measurements for the input parameters. The model was applied to a total of 623 discovery molecules and their oral exposure was predicted in rats and/or dogs. The predictions of Cmax, AUClast and Tmax were compared against the observations.
Results. The generic model proved to make predictions of oral Cmax, AUClast and Tmax within 3-fold of the observations for rats in respectively 65%, 68% and 57% of the 537 cases. For dogs, it was respectively 77%, 79% and 85% of the 124 cases. Statistically, the model was most successful at predicting oral exposure of Biopharmaceutical Classification System (BCS) class 1 compounds compared to classes 2 and 3, and was worst at predicting oral exposure of BCS class 4 compounds.
Conclusion. The generic Gastroplus ACAT model provided reasonable predictions especially for BCS class 1 compounds. For compounds of other classes, the model may be refined by obtaining more information on solubility and permeability in secondary assays, e.g. solubility in rat simulated fluids. This increases confidence that such a model can be used in discovery projects to understand the parameters limiting absorption and extrapolate predictions across species. Also, when predictions disagree with the observations, the model can be updated to test hypotheses. This can help identify the most likely mechanism driving the absorption and thus design the relevant experiments to understand absorption.

Item Type: Article
Keywords: pharmacokinetics; ADME; oral absorption; rat; dog; physiologically based pharmacokinetics (PBPK); advanced compartmental and transit (ACAT); Gastroplus; drug discovery.
Date Deposited: 12 Oct 2016 00:45
Last Modified: 12 Oct 2016 00:45
URI: https://oak.novartis.com/id/eprint/29350

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