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Pharmaceutical Research

, Volume 33, Issue 9, pp 2126–2139 | Cite as

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

  • N. Gobeau
  • R. Stringer
  • S. De Buck
  • T. Tuntland
  • B. Faller
Research Paper

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.

KEY WORDS

advanced compartmental and transit (ACAT) drug discovery GastroPlus oral absorption physiologically based pharmacokinetics (PBPK) 

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

Notes

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.

Supplementary material

11095_2016_1951_MOESM1_ESM.docx (405 kb)
ESM 1 (DOCX 405 kb)
11095_2016_1951_MOESM2_ESM.xlsx (1.1 mb)
ESM 2 (XLSX 1.09 mb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • N. Gobeau
    • 1
    • 2
  • R. Stringer
    • 1
  • S. De Buck
    • 3
  • T. Tuntland
    • 4
  • B. Faller
    • 1
  1. 1.Metabolism and Pharmacokinetics (MAP) DepartmentNovartis Institutes for Biomedical ResearchBaselSwitzerland
  2. 2.Medicines for Malaria VentureGeneva 15Switzerland
  3. 3.Drug Metabolism and Pharmacokinetics (DMPK) DepartmentNovartis Institutes for Biomedical ResearchBaselSwitzerland
  4. 4.Metabolism and Pharmacokinetics (MAP) DepartmentGenomics Institute of the Novartis Foundation, Novartis Institutes for Biomedical ResearchSan DiegoUSA

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