Pharmaceutical Research

, Volume 31, Issue 9, pp 2367–2382 | Cite as

Reduced Physiologically-Based Pharmacokinetic Model of Repaglinide: Impact of OATP1B1 and CYP2C8 Genotype and Source of In Vitro Data on the Prediction of Drug-Drug Interaction Risk

  • Michael Gertz
  • Nikolaos Tsamandouras
  • Carolina Säll
  • J. Brian Houston
  • Aleksandra Galetin
Research Paper



To investigate the effect of OATP1B1 genotype as a covariate on repaglinide pharmacokinetics and drug-drug interaction (DDIs) risk using a reduced physiologically-based pharmacokinetic (PBPK) model.


Twenty nine mean plasma concentration-time profiles for SLCO1B1 c.521T>C were used to estimate hepatic uptake clearance (CLuptake) in different genotype groups applying a population approach in NONMEM v.7.2.


Estimated repaglinide CLuptake corresponded to 217 and 113 μL/min/106 cells for SLCO1B1 c.521TT/TC and CC, respectively. A significant effect of OATP1B1 genotype was seen on CLuptake (48% reduction for CC relative to wild type). Sensitivity analysis highlighted the impact of CLmet and CLdiff uncertainty on the CLuptake optimization using plasma data. Propagation of this uncertainty had a marginal effect on the prediction of repaglinide OATP1B1-mediated DDI with cyclosporine; however, sensitivity of the predicted magnitude of repaglinide metabolic DDI was high. In addition, the reduced PBPK model was used to assess the effect of both CYP2C8*3 and SLCO1B1 c.521T>C on repaglinide exposure by simulations; power calculations were performed to guide prospective DDI and pharmacogenetic studies.


The application of reduced PBPK model for parameter optimization and limitations of this process associated with the use of plasma rather than tissue profiles are illustrated.


drug-drug interactions OATP1B1 physiologically-based pharmacokinetic models repaglinide 


Acknowledgments and DISCLOSURES

The work was funded by a consortium of pharmaceutical companies within the Centre for Applied Pharmacokinetic Research, University of Manchester (

NT is a recipient of a PhD studentship from University of Manchester and Eli Lilly and Company, Indianapolis, USA.

Supplementary material

11095_2014_1333_MOESM1_ESM.docx (855 kb)
ESM 1 (DOCX 855 kb)


  1. 1.
    Jones H, Rowland-Yeo K. Basic concepts in physiologically based pharmacokinetic modeling in drug discovery and development. CPT Pharmacometrics Syst Pharmacol. 2013;2:e63.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Rostami-Hodjegan A. Physiologically based pharmacokinetics joined with in vitro-in vivo extrapolation of adme: a marriage under the arch of systems pharmacology. Clin Pharmacol Ther. 2012;92:50–61.PubMedCrossRefGoogle Scholar
  3. 3.
    Gertz M, Houston JB, Galetin A. Physiologically based pharmacokinetic modeling of intestinal first-pass metabolism of CYP3A substrates with high intestinal extraction. Drug Metab Dispos. 2011;39:1633–42.PubMedCrossRefGoogle Scholar
  4. 4.
    Gertz M, Cartwright CM, Hobbs MJ, Kenworthy KE, Rowland M, Houston JB, et al. Application of PBPK modeling in the assessment of the interaction potential of cyclosporine against hepatic and intestinal uptake and efflux transporters and CYP3A4. Pharm Res. 2013;30:761–80.PubMedCrossRefGoogle Scholar
  5. 5.
    Varma MV, Lai Y, Kimoto E, Goosen TC, El-Kattan AF, Kumar V. Mechanistic modeling to predict the transporter- and enzyme-mediated drug-drug interactions of repaglinide. Pharm Res. 2013;30:1188–99.PubMedCrossRefGoogle Scholar
  6. 6.
    Zamek-Gliszczynski MJ, Lee CA, Poirier A, Bentz J, Chu X, Ishikawa T, et al. ITC recommendations on transporter kinetic parameter estimation and translational modeling of transport-mediated PK and DDIs in humans. Clin Pharmacol Ther. 2013;94(1):64–79.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Jones HM, Barton HA, Lai Y, Bi YA, Kimoto E, Kempshall S, et al. Mechanistic pharmacokinetic modeling for the prediction of transporter-mediated disposition in humans from sandwich culture human hepatocyte data. Drug Metab Dispos. 2012;40:1007–17.PubMedCrossRefGoogle Scholar
  8. 8.
    Poirier A, Funk C, Scherrmann JM, Lave T. Mechanistic modeling of hepatic transport from cells to whole body: application to napsagatran and fexofenadine. Mol Pharm. 2009;6:1716–33.PubMedCrossRefGoogle Scholar
  9. 9.
    Watanabe T, Kusuhara H, Maeda K, Shitara Y, Sugiyama Y. Physiologically based pharmacokinetic modeling to predict transporter-mediated clearance and distribution of pravastatin in humans. J Pharmacol Exp Ther. 2009;328:652–62.PubMedCrossRefGoogle Scholar
  10. 10.
    Kusuhara H, Sugiyama Y. Pharmacokinetic modeling of the hepatobiliary transport mediated by cooperation of uptake and efflux transporters. Drug Metab Rev. 2010;42:539–50.PubMedCrossRefGoogle Scholar
  11. 11.
    Shitara Y, Maeda K, Ikejiri K, Yoshida K, Horie T, Sugiyama Y. Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption. Biopharm Drug Dispos. 2013;34:45–78.PubMedCrossRefGoogle Scholar
  12. 12.
    Poirier A, Lave T, Portmann R, Brun ME, Senner F, Kansy M, et al. Design, data analysis, and simulation of in vitro drug transport kinetic experiments using a mechanistic in vitro model. Drug Metab Dispos. 2008;36:2434–44.PubMedCrossRefGoogle Scholar
  13. 13.
    Paine SW, Parker AJ, Gardiner P, Webborn PJ, Riley RJ. Prediction of the pharmacokinetics of atorvastatin, cerivastatin, and indomethacin using kinetic models applied to isolated rat hepatocytes. Drug Metab Dispos. 2008;36:1365–74.PubMedCrossRefGoogle Scholar
  14. 14.
    Menochet K, Kenworthy KE, Houston JB, Galetin A. Simultaneous assessment of uptake and metabolism in rat hepatocytes: a comprehensive mechanistic model. J Pharmacol Exp Ther. 2012;341:2–15.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Menochet K, Kenworthy KE, Houston JB, Galetin A. Use of mechanistic modelling to assess inter-individual variability and inter-species differences in active uptake in human and rat hepatocytes. Drug Metab Dispos. 2012;40:1744–56.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Lee JK, Marion TL, Abe K, Lim C, Pollock GM, Brouwer KL. Hepatobiliary disposition of troglitazone and metabolites in rat and human sandwich-cultured hepatocytes: use of Monte Carlo simulations to assess the impact of changes in biliary excretion on troglitazone sulfate accumulation. J Pharmacol Exp Ther. 2010;332:26–34.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Yabe Y, Galetin A, Houston JB. Kinetic characterization of rat hepatic uptake of 16 actively transported drugs. Drug Metab Dispos. 2011;39:1808–14.PubMedCrossRefGoogle Scholar
  18. 18.
    Nordell P, Winiwarter S, Hilgendorf C. Resolving the distribution-metabolism interplay of eight OATP substrates in the standard clearance assay with suspended human cryopreserved hepatocytes. Mol Pharm. 2013;10:4443–51.PubMedCrossRefGoogle Scholar
  19. 19.
    Camenisch G, Umehara K. Predicting human hepatic clearance from in vitro drug metabolism and transport data: a scientific and pharmaceutical perspective for assessing drug-drug interactions. Biopharm Drug Dispos. 2012;33:179–94.PubMedCrossRefGoogle Scholar
  20. 20.
    Hallifax D, Foster JA, Houston JB. Prediction of human metabolic clearance from in vitro systems: retrospective analysis and prospective view. Pharm Res. 2010;27:2150–61.PubMedCrossRefGoogle Scholar
  21. 21.
    Badolo L, Rasmussen LM, Hansen HR, Sveigaard C. Screening of OATP1B1/3 and OCT1 inhibitors in cryopreserved hepatocytes in suspension. Eur J Pharm Sci. 2011;40:282–8.CrossRefGoogle Scholar
  22. 22.
    Ulvestad M, Bjorquist P, Molden E, Asberg A, Andersson TB. OATP1B1/1B3 activity in plated primary human hepatocytes over time in culture. Biochem Pharmacol. 2011;82:1219–26.PubMedCrossRefGoogle Scholar
  23. 23.
    Kimoto E, Yoshida K, Balogh LM, Bi YA, Maeda K, El-Kattan A, et al. Characterization of organic anion transporting polypeptide (OATP) expression and its functional contribution to the uptake of substrates in human hepatocytes. Mol Pharm. 2012;9:3535–42.PubMedCrossRefGoogle Scholar
  24. 24.
    Ohtsuki S, Schaefer O, Kawakami H, Inoue T, Liehner S, Saito A, et al. Simultaneous absolute protein quantification of transporters, cytochromes P450, and UDP-glucuronosyltransferases as a novel approach for the characterization of individual human liver: comparison with mRNA levels and activities. Drug Metab Dispos. 2012;40:83–92.PubMedCrossRefGoogle Scholar
  25. 25.
    van de Steeg E, Greupink R, Schreurs M, Nooijen IH, Verhoeckx KC, Hanemaaijer R, et al. Drug-drug interactions between rosuvastatin and oral antidiabetic drugs occurring at the level of OATP1B1. Drug Metab Dispos. 2013;41:592–601.PubMedCrossRefGoogle Scholar
  26. 26.
    Tsamandouras N, Rostami-Hodjegan A, Aarons L. Combining the “bottom-up” and “top-down” approaches in pharmacokinetic modelling: Fitting PBPK models to observed clinical data. Br J Clin Pharmacol. 2013.Google Scholar
  27. 27.
    Sall C, Houston JB, Galetin A. A comprehensive assessment of repaglinide metabolic pathways: impact of choice of in vitro system and relative enzyme contribution to in vitro clearance. Drug Metab Dispos. 2012;40:1279–89.PubMedCrossRefGoogle Scholar
  28. 28.
    Niemi M, Backman JT, Kajosaari LI, Leathart JB, Neuvonen M, Daly AK, et al. Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin Pharmacol Ther. 2005;77:468–78.PubMedCrossRefGoogle Scholar
  29. 29.
    Bidstrup TB, Damkier P, Olsen AK, Ekblom M, Karlsson A, Brosen K. The impact of CYP2C8 polymorphism and grapefruit juice on the pharmacokinetics of repaglinide. Br J Clin Pharmacol. 2006;61:49–57.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Tomalik-Scharte D, Fuhr U, Hellmich M, Frank D, Doroshyenko O, Jetter A, et al. Effect of the CYP2C8 genotype on the pharmacokinetics and pharmacodynamics of repaglinide. Drug Metab Dispos. 2011;39:927–32.PubMedCrossRefGoogle Scholar
  31. 31.
    Niemi M, Leathart JB, Neuvonen M, Backman JT, Daly AK, Neuvonen PJ. Polymorphism in CYP2C8 is associated with reduced plasma concentrations of repaglinide. Clin Pharmacol Ther. 2003;74:380–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Kalliokoski A, Neuvonen M, Neuvonen PJ, Niemi M. The effect of SLCO1B1 polymorphism on repaglinide pharmacokinetics persists over a wide dose range. Br J Clin Pharmacol. 2008;66:818–25.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Quinney SK, Zhang X, Lucksiri A, Gorski JC, Li L, Hall SD. Physiologically based pharmacokinetic model of mechanism-based inhibition of CYP3A by clarithromycin. Drug Metab Dispos. 2010;38:241–8.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Ito K, Ogihara K, Kanamitsu S, Itoh T. Prediction of the in vivo interaction between midazolam and macrolides based on in vitro studies using human liver microsomes. Drug Metab Dispos. 2003;31:945–54.PubMedCrossRefGoogle Scholar
  35. 35.
    Cao Y, Jusko WJ. Applications of minimal physiologically-based pharmacokinetic models. J Pharmacokinet Pharmacodyn. 2012;39:711–23.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011;63:157–81.PubMedCrossRefGoogle Scholar
  37. 37.
    van Heiningen PN, Hatorp V, Kramer Nielsen K, Hansen KT, van Lier JJ, De Merbel NC, et al. Absorption, metabolism and excretion of a single oral dose of (14)C-repaglinide during repaglinide multiple dosing. Eur J Clin Pharmacol. 1999;55:521–5.PubMedCrossRefGoogle Scholar
  38. 38.
    Honkalammi J, Niemi M, Neuvonen PJ, Backman JT. Dose-dependent interaction between gemfibrozil and repaglinide in humans: strong inhibition of CYP2C8 with subtherapeutic gemfibrozil doses. Drug Metab Dispos. 2011;39:1977–86.PubMedCrossRefGoogle Scholar
  39. 39.
    Tornio A, Niemi M, Neuvonen M, Laitila J, Kalliokoski A, Neuvonen PJ, et al. The effect of gemfibrozil on repaglinide pharmacokinetics persists for at least 12 h after the dose: evidence for mechanism-based inhibition of CYP2C8 in vivo. Clin Pharmacol Ther. 2008;84:403–11.PubMedCrossRefGoogle Scholar
  40. 40.
    Gertz M, Harrison A, Houston JB, Galetin A. Prediction of human intestinal first-pass metabolism of 25 CYP3A substrates from in vitro clearance and permeability data. Drug Metab Dispos. 2010;38:1147–58.PubMedCrossRefGoogle Scholar
  41. 41.
    Bellu G, Saccomani MP, Audoly S, D’Angio L. DAISY: a new software tool to test global identifiability of biological and physiological systems. Comput Methods Prog Biomed. 2007;88:52–61.CrossRefGoogle Scholar
  42. 42.
    Gertz M, Davis JD, Harrison A, Houston JB, Galetin A. Grapefruit juice-drug interaction studies as a method to assess the extent of intestinal availability: utility and limitations. Curr Drug Metab. 2008;9:785–95.PubMedCrossRefGoogle Scholar
  43. 43.
    Bidstrup TB, Bjornsdottir I, Sidelmann UG, Thomsen MS, Hansen KT. CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide. Br J Clin Pharmacol. 2003;56:305–14.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Gallo JM, Lam FC, Perrier DG. Area method for the estimation of partition coefficients for physiological pharmacokinetic models. J Pharmacokinet Biopharm. 1987;15:271–80.PubMedCrossRefGoogle Scholar
  45. 45.
    Backman JT, Honkalammi J, Neuvonen M, Kurkinen KJ, Tornio A, Niemi M, et al. CYP2C8 activity recovers within 96 hours after gemfibrozil dosing: estimation of CYP2C8 half-life using repaglinide as an in vivo probe. Drug Metab Dispos. 2009;37:2359–66.PubMedCrossRefGoogle Scholar
  46. 46.
    Yu L, Shi D, Ma L, Zhou Q, Zeng S. Influence of CYP2C8 polymorphisms on the hydroxylation metabolism of paclitaxel, repaglinide and ibuprofen enantiomers in vitro. Biopharm Drug Dispos. 2013;34:278–87.PubMedCrossRefGoogle Scholar
  47. 47.
    Bahadur N, Leathart JB, Mutch E, Steimel-Crespi D, Dunn SA, Gilissen R, et al. CYP2C8 polymorphisms in Caucasians and their relationship with paclitaxel 6alpha-hydroxylase activity in human liver microsomes. Biochem Pharmacol. 2002;64:1579–89.PubMedCrossRefGoogle Scholar
  48. 48.
    Dai D, Zeldin DC, Blaisdell JA, Chanas B, Coulter SJ, Ghanayem BI, et al. Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics. 2001;11:597–607.PubMedCrossRefGoogle Scholar
  49. 49.
    Hatorp V, Oliver S, Su CA. Bioavailability of repaglinide, a novel antidiabetic agent, administered orally in tablet or solution form or intravenously in healthy male volunteers. Int J Clin Pharmacol Ther. 1998;36:636–41.PubMedGoogle Scholar
  50. 50.
    Quinney SK, Galinsky RE, Jiyamapa-Serna VA, Chen Y, Hamman MA, Hall SD, et al. Hydroxyitraconazole, formed during intestinal first-pass metabolism of itraconazole, controls the time course of hepatic CYP3A inhibition and the bioavailability of itraconazole in rats. Drug Metab Dispos. 2008;36:1097–101.PubMedCrossRefGoogle Scholar
  51. 51.
    Kudo T, Hisaka A, Sugiyama Y, Ito K. Analysis of the repaglinide concentration increase produced by gemfibrozil and itraconazole based on the inhibition of the hepatic uptake transporter and metabolic enzymes. Drug Metab Dispos. 2013;41:362–71.PubMedCrossRefGoogle Scholar
  52. 52.
    Varma MV, Lin J, Bi YA, Rotter CJ, Fahmi OA, Lam JL, et al. Quantitative prediction of repaglinide-rifampicin complex drug interactions using dynamic and static mechanistic models: delineating differential CYP3A4 induction and OATP1B1 inhibition potential of rifampicin. Drug Metab Dispos. 2013;41:966–74.PubMedCrossRefGoogle Scholar
  53. 53.
    Williams JA, Johnson K, Paulauskis J, Cook J. So many studies, too few subjects: establishing functional relevance of genetic polymorphisms on pharmacokinetics. J Clin Pharmacol. 2006;46:258–64.PubMedCrossRefGoogle Scholar
  54. 54.
    International Commission on Radiological Protection. Basic anatomical and physiological data for use in radiological protection: reference values. A report of age- and gender-related differences in the anatomical and physiological characteristics of reference individuals. ICRP Publication 89. Ann ICRP. 2002;32:5–265.CrossRefGoogle Scholar
  55. 55.
    Hatorp V, Walther KH, Christensen MS, Haug-Pihale G. Single-dose pharmacokinetics of repaglinide in subjects with chronic liver disease. J Clin Pharmacol. 2000;40:142–52.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Michael Gertz
    • 1
    • 2
  • Nikolaos Tsamandouras
    • 1
  • Carolina Säll
    • 1
  • J. Brian Houston
    • 1
  • Aleksandra Galetin
    • 1
  1. 1.Centre for Applied Pharmacokinetic Research Manchester Pharmacy SchoolThe University of ManchesterManchesterUK
  2. 2.F. Hoffmann-La Roche, Modelling and SimulationPharmaceutical Sciences pREDBaselSwitzerland

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