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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 6/2020

01-06-2020 | Breast Cancer | Original Research Article

Quantitative Prediction of Interactions Mediated by Transporters and Cytochromes: Application to Organic Anion Transporting Polypeptides, Breast Cancer Resistance Protein and Cytochrome 2C8

Authors: Michel Tod, Laurent Bourguignon, Nathalie Bleyzac, Sylvain Goutelle

Published in: Clinical Pharmacokinetics | Issue 6/2020

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Abstract

Background

The in vivo mechanistic static model (IMSM) is an effective method to predict the magnitude of drug–drug interactions (DDIs) mediated by cytochromes.

Objective

The aim of this study was to extend the IMSM paradigm to DDIs mediated by organic anion transporting polypeptide (OATP) 1Bs, breast cancer resistance protein (BCRP) and cytochrome 2C8.

Methods

First, a generic model for this kind of interaction was established, and a literature search was then conducted to retrieve the area under the concentration–time curve (AUC) ratio of a large set of DDIs involving OATP1B1, OATP1B3, BCRP and cytochromes 2C8 or 3A4. The model was fitted to the data to estimate the characteristic parameters (contribution ratios [CRs] and inhibition or induction potencies [IXs]) by nonlinear regression, and the model was qualified by external validation on a different dataset. Lastly, the model was used to identify the risks of overexposure by DDIs of this type.

Results

A total of 27 substrates, 26 inhibitors, 3 inducers and 3 genetic variants were considered in the regression analysis. The number of observations (AUC ratios, denoted as Robs) was 101. Forty-six CRs and 47 IXs were estimated. The proportions of predictions within 0.67- to 1.5-fold and 0.5- to twofold Robs were 90% and 99%, respectively, for the internal validation, and 78% and 96%, respectively, for the external validation. The median fold-error was 1.03 (the ideal value is 1). The interquartile range of fold-error was 0.31, and the relative standard error of parameter estimates was, at most, 17%.

Conclusions

The IMSM approach was successfully extended to DDIs mediated by OATP1Bs, BCRP and cytochromes 2C8 or 3A4. The method revealed good predictive performances by internal and external validation.
Appendix
Available only for authorised users
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Metadata
Title
Quantitative Prediction of Interactions Mediated by Transporters and Cytochromes: Application to Organic Anion Transporting Polypeptides, Breast Cancer Resistance Protein and Cytochrome 2C8
Authors
Michel Tod
Laurent Bourguignon
Nathalie Bleyzac
Sylvain Goutelle
Publication date
01-06-2020
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 6/2020
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-019-00853-2

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