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Cited by 67Drug Solubulity and Delivery SystemsComputational Drug Discovery MethodsPharmacogenetics and Drug Metabolism

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

Gobeau, N., Stringer, R., De Buck, S., Tuntland, T., Faller, B.·2016·Pharmaceutical Research
DOI 10.1007/s11095-016-1951-z
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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 (as determined by PAMPA, solubility, liver microsomal stability assays).Methods 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 class 4 compounds oral exposure.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. 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.

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Authors
Gobeau, N., Stringer, R., De Buck, S., Tuntland, T., & Faller, B.
Affiliations
  • Novartis (Switzerland) (CH)
  • Genomics Institute of the Novartis Research Foundation (US)
Corresponding author
Gobeau, N.
ORCID
Venue
Pharmaceutical Research
Publisher
Springer Science and Business Media LLC
Published
2016-06-08
Volume
33
Issue
9
Pages
2126-2139
ISSN
  • 0724-8741 (ISSN-L)
  • 1573-904X
DOI
10.1007/s11095-016-1951-z
OpenAlex
W2417297292
Cited by
67
References
36
Citations by year
2026: 6 · 2025: 7 · 2024: 8 · 2023: 8 · 2022: 8 · 2021: 6 · 2020: 8 · 2019: 7 · 2018: 7 · 2017: 2
FWCI
3.04
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (unspecified)
Locations
  • Pharmaceutical Research (publishedVersion)
  • PubMed (publishedVersion)
  • The Novartis Repository (Novartis) (submittedVersion)
Funders
  • Novartis Pharma
  • Novartis Institutes for BioMedical Research
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
early drug discovery, Biopharmaceutics Classification System, Pampas, solubility, permeability, interspecies extrapolation
MeSH terms
Animals, Computer Simulation, Dogs, Pharmaceutical Preparations, Humans, Intestinal Absorption, Male, Models, Biological, Permeability, Solubility, Rats, Sprague-Dawley, Rats, Drug Discovery

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