Evaluation of the GastroPlus™ Advanced Compartmental and Transit (ACAT) Model in Early Discovery
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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.
KEY WORDSadvanced compartmental and transit (ACAT) drug discovery GastroPlus oral absorption physiologically based pharmacokinetics (PBPK)
Advanced compartmental and transit
Absorption, distribution, metabolism, excretion
- AFE abs
Absolute average fold error
- AFE rel
Relative average fold error
Absorption scaling factor
Area under the curve
Area under the curve to the last time point
Biopharmaceutical classification system
Buffer solubility at a given pH
Solubility in the presence of bile salt at a given pH
Human fasted simulated intestinal fluid
Liquid chromatography tandem mass spectometry
Madin Darby canine kidney
Microsomal protein per gram liver
Novartis institutes for biomedical research
Parallel artifical membrane permeability assay
Physiologically based pharmacokinetics
Polar surface area
Hepatic blood flow
Aqueous solubilization ratio
Simulated intestinal fluid
Bile salt solubilization ratio
Time at which the concentration is maximum
ACKNOWLEDGMENTS AND DISCLOSURES
The authors would like to thank all colleagues from Metabolism and Pharmacokinetics at NIBR and GNF, Global Discovery Chemistry and Analytical Sciences and Imaging who provided the critical data and their interpretation to build and evaluate the model. Also, the authors are grateful for the support and useful discussions with Pankaj Daga and Eric Martin, in NIBR Computer Aided Drug Discovery, and Gérard Flesch, in Novartis Pharma Integrated Quantitative Science.
This study was supported by NIBR. The authors have no conflicts of interest directly relevant to the content of this study.
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