Evaluation of the GastroPlus™ Advanced Compartmental and Transit (ACAT) Model in Early Discovery.
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 (as determined by PAMPA, solubility, liver microsomal stability assays).



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.



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 class 4 compounds oral exposure.



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. 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 and understand oral absorption.
Metabolism and Pharmacokinetics (MAP) Department, Novartis Institutes for Biomedical Research, Basel, Switzerland. gobeaun@mmv.org.|Medicines for Malaria Venture, Route de Pré-Bois 20, PO Box 1826, 1215, Geneva 15, Switzerland. gobeaun@mmv.org.
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Gobeau
Metabolism and Pharmacokinetics (MAP) Department, Novartis Institutes for Biomedical Research, Basel, Switzerland.
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Stringer
Drug Metabolism and Pharmacokinetics (DMPK) Department, Novartis Institutes for Biomedical Research, Basel, Switzerland.
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De Buck
Metabolism and Pharmacokinetics (MAP) Department, Genomics Institute of the Novartis Foundation, Novartis Institutes for Biomedical Research, San Diego, California, USA.
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Tuntland
Metabolism and Pharmacokinetics (MAP) Department, Novartis Institutes for Biomedical Research, Basel, Switzerland.
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Faller
D000818:Animals; D003198:Computer Simulation; D004285:Dogs; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology; D008297:Male; D008954:Models, Biological; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
D004364:Pharmaceutical Preparations
GastroPlus; advanced compartmental and transit (ACAT); drug discovery; oral absorption; physiologically based pharmacokinetics (PBPK)