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Pharmaceutical Research

, Volume 30, Issue 4, pp 1188–1199 | Cite as

Mechanistic Modeling to Predict the Transporter- and Enzyme-Mediated Drug-Drug Interactions of Repaglinide

  • Manthena V. S. Varma
  • Yurong Lai
  • Emi Kimoto
  • Theunis C. Goosen
  • Ayman F. El-Kattan
  • Vikas Kumar
Research Paper

ABSTRACT

Purpose

Quantitative prediction of complex drug-drug interactions (DDIs) is challenging. Repaglinide is mainly metabolized by cytochrome-P-450 (CYP)2C8 and CYP3A4, and is also a substrate of organic anion transporting polypeptide (OATP)1B1. The purpose is to develop a physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics and DDIs of repaglinide.

Methods

In vitro hepatic transport of repaglinide, gemfibrozil and gemfibrozil 1-O-β-glucuronide was characterized using sandwich-culture human hepatocytes. A PBPK model, implemented in Simcyp (Sheffield, UK), was developed utilizing in vitro transport and metabolic clearance data.

Results

In vitro studies suggested significant active hepatic uptake of repaglinide. Mechanistic model adequately described repaglinide pharmacokinetics, and successfully predicted DDIs with several OATP1B1 and CYP3A4 inhibitors (<10% error). Furthermore, repaglinide-gemfibrozil interaction at therapeutic dose was closely predicted using in vitro fraction metabolism for CYP2C8 (0.71), when primarily considering reversible inhibition of OATP1B1 and mechanism-based inactivation of CYP2C8 by gemfibrozil and gemfibrozil 1-O-β-glucuronide.

Conclusions

This study demonstrated that hepatic uptake is rate-determining in the systemic clearance of repaglinide. The model quantitatively predicted several repaglinide DDIs, including the complex interactions with gemfibrozil. Both OATP1B1 and CYP2C8 inhibition contribute significantly to repaglinide-gemfibrozil interaction, and need to be considered for quantitative rationalization of DDIs with either drug.

KEY WORDS

CYP2C8 drug-drug interaction gemfibrozil OATP1B1 physiologically-based pharmacokinetic model repaglinide 

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to thank Drs. Larissa Balogh and Larry Tremaine for comments and insightful discussion on the content of this manuscript.

All authors are full-time employees of Pfizer Inc. Constructive suggestions by the reviewers during revision are greatly appreciated. The authors have no conflicts of interest that are directly relevant to this study.

Supplementary material

11095_2012_956_MOESM1_ESM.docx (286 kb)
ESM 1 (DOCX 286 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Manthena V. S. Varma
    • 1
  • Yurong Lai
    • 1
  • Emi Kimoto
    • 1
  • Theunis C. Goosen
    • 1
  • Ayman F. El-Kattan
    • 1
  • Vikas Kumar
    • 2
  1. 1.Pharmacokinetcis, Dynamics and Metabolism, Pfizer Inc.GrotonUSA
  2. 2.Clincial Pharmacology, Pfizer Inc.GrotonUSA

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