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

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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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Abbreviations

ACAT:

Advanced compartmental and transit

ADME:

Absorption, distribution, metabolism, excretion

AFE abs:

Absolute average fold error

AFE rel:

Relative average fold error

ASF:

Absorption scaling factor

AUC:

Area under the curve

AUClast :

Area under the curve to the last time point

BCS:

Biopharmaceutical classification system

CLint :

Intrinsic clearance

Cmax :

Maximum concentration

Cs,buffer,pH :

Buffer solubility at a given pH

Cs,GI,pH :

Solubility in the presence of bile salt at a given pH

FaSSIF:

Human fasted simulated intestinal fluid

GI:

Gastrointestinal

IV:

Intravenous

LC-MS/MS:

Liquid chromatography tandem mass spectometry

LW:

liver weight

MDCK:

Madin Darby canine kidney

MPPGL:

Microsomal protein per gram liver

MW:

Molecular weight

NIBR:

Novartis institutes for biomedical research

PAMPA:

Parallel artifical membrane permeability assay

PBPK:

Physiologically based pharmacokinetics

Peff:

Effective permeability

PK:

Pharmacokinetic

PO :

Per Os

PSA:

Polar surface area

Qh :

Hepatic blood flow

Saq :

Aqueous solubilization ratio

SIF:

Simulated intestinal fluid

SR:

Bile salt solubilization ratio

Tmax :

Time at which the concentration is maximum

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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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Author notes

  1. N. Gobeau

    Present address: Medicines for Malaria Venture, Route de Pré-Bois 20, PO Box 1826, 1215, Geneva 15, Switzerland

Authors and Affiliations

  1. Metabolism and Pharmacokinetics (MAP) Department, Novartis Institutes for Biomedical Research, Basel, Switzerland

    N. Gobeau, R. Stringer & B. Faller

  2. Drug Metabolism and Pharmacokinetics (DMPK) Department, Novartis Institutes for Biomedical Research, Basel, Switzerland

    S. De Buck

  3. Metabolism and Pharmacokinetics (MAP) Department, Genomics Institute of the Novartis Foundation, Novartis Institutes for Biomedical Research, San Diego, California, USA

    T. Tuntland

Authors
  1. N. Gobeau
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  4. T. Tuntland
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  5. B. Faller
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Correspondence to N. Gobeau.

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Gobeau, N., Stringer, R., De Buck, S. et al. Evaluation of the GastroPlus™ Advanced Compartmental and Transit (ACAT) Model in Early Discovery. Pharm Res 33, 2126–2139 (2016). https://doi.org/10.1007/s11095-016-1951-z

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  • DOI: https://doi.org/10.1007/s11095-016-1951-z

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