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

Clin Pharmacokinet. 2020 Jun;59(6):757-770. doi: 10.1007/s40262-019-00853-2.

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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Breast Neoplasms* / metabolism
  • Cytochromes / metabolism*
  • Drug Interactions
  • Female
  • Humans
  • Liver-Specific Organic Anion Transporter 1
  • Neoplasm Proteins / metabolism
  • Organic Anion Transporters / metabolism*
  • Peptides
  • Solute Carrier Organic Anion Transporter Family Member 1B3

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Cytochromes
  • Liver-Specific Organic Anion Transporter 1
  • Neoplasm Proteins
  • Organic Anion Transporters
  • Peptides
  • SLCO1B1 protein, human
  • SLCO1B3 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3