Quantitative Analysis of Complex Drug-Drug Interactions Between Repaglinide and Cyclosporin A/Gemfibrozil Using Physiologically Based Pharmacokinetic Models With In Vitro Transporter/Enzyme Inhibition Data.

Quantitative analysis of transporter- and enzyme-mediated complex drug-drug interactions (DDIs) is challenging. Repaglinide (RPG) is transported into the liver by OATP1B1 and then is metabolized by CYP2C8 and CYP3A4. The purpose of this study was to describe the complex DDIs of RPG quantitatively based on unified physiologically based pharmacokinetic (PBPK) models using in vitro Ki values for OATP1B1, CYP3A4, and CYP2C8. Cyclosporin A (CsA) or gemfibrozil (GEM) increased the blood concentrations of RPG. The time profiles of RPG and the inhibitors were analyzed by PBPK models, considering the inhibition of OATP1B1 and CYP3A4 by CsA or OATP1B1 inhibition by GEM and its glucuronide and the mechanism-based inhibition of CYP2C8 by GEM glucuronide. RPG-CsA interaction was closely predicted using a reported in vitro Ki,OATP1B1 value in the presence of CsA preincubation. RPG-GEM interaction was underestimated compared with observed data, but the simulation was improved with the increase of fm,CYP2C8. These results based on in vitro Ki values for transport and metabolism suggest the possibility of a bottom-up approach with in vitro inhibition data for the prediction of complex DDIs using unified PBPK models and in vitro fm value of a substrate for multiple enzymes should be considered carefully for the prediction.

[1]  Yuichi Sugiyama,et al.  Virtual Clinical Studies to Examine the Probability Distribution of the AUC at Target Tissues Using Physiologically-Based Pharmacokinetic Modeling: Application to Analyses of the Effect of Genetic Polymorphism of Enzymes and Transporters on Irinotecan Induced Side Effects , 2017, Pharmaceutical Research.

[2]  M. Hirano,et al.  INTERACTION BETWEEN FIBRATES AND STATINS - METABOLIC INTERACTIONS WITH GEMFIBROZIL , 2003, Drug metabolism and drug interactions.

[3]  M. Niemi,et al.  Gemfibrozil Is a Strong Inactivator of CYP2C8 in Very Small Multiple Doses , 2012, Clinical pharmacology and therapeutics.

[4]  Kazuya Maeda,et al.  Clarification of the Mechanism of Clopidogrel-Mediated Drug–Drug Interaction in a Clinical Cassette Small-dose Study and Its Prediction Based on In Vitro Information , 2016, Drug Metabolism and Disposition.

[5]  P. Neuvonen,et al.  Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide , 2003, Diabetologia.

[6]  L. Wienkers,et al.  Selection of Alternative CYP3A4 Probe Substrates for Clinical Drug Interaction Studies Using In Vitro Data and In Vivo Simulation , 2010, Drug Metabolism and Disposition.

[7]  Kazuya Maeda,et al.  Physiologically Based Pharmacokinetic Modeling to Predict Transporter-Mediated Clearance and Distribution of Pravastatin in Humans , 2009, Journal of Pharmacology and Experimental Therapeutics.

[8]  A. D. Rodrigues,et al.  Quantitative Rationalization of Gemfibrozil Drug Interactions: Consideration of Transporters-Enzyme Interplay and the Role of Circulating Metabolite Gemfibrozil 1-O-β-Glucuronide , 2015, Drug Metabolism and Disposition.

[9]  Akihiko Konagaya,et al.  Estimation of feasible solution space using Cluster Newton Method: application to pharmacokinetic analysis of irinotecan with physiologically-based pharmacokinetic models , 2013, BMC Systems Biology.

[10]  P. Neuvonen,et al.  Telithromycin, but not montelukast, increases the plasma concentrations and effects of the cytochrome P450 3A4 and 2C8 substrate repaglinide , 2006, Clinical pharmacology and therapeutics.

[11]  A. Y. Lu,et al.  Inhibition and Induction of Cytochrome P450 and the Clinical Implications , 1998, Clinical pharmacokinetics.

[12]  K. Maeda,et al.  Investigation of the Impact of Substrate Selection on In Vitro Organic Anion Transporting Polypeptide 1B1 Inhibition Profiles for the Prediction of Drug-Drug Interactions , 2015, Drug Metabolism and Disposition.

[13]  H. Kamimura,et al.  The UDP-Glucuronosyltransferase 2B7 Isozyme Is Responsible for Gemfibrozil Glucuronidation in the Human Liver , 2007, Drug Metabolism and Disposition.

[14]  Yuichi Sugiyama,et al.  Analysis of the Repaglinide Concentration Increase Produced by Gemfibrozil and Itraconazole Based on the Inhibition of the Hepatic Uptake Transporter and Metabolic Enzymes , 2013, Drug Metabolism and Disposition.

[15]  Kiyomi Ito,et al.  Estimation of the Contribution of CYP2C8 and CYP3A4 in Repaglinide Metabolism by Human Liver Microsomes Under Various Buffer Conditions. , 2017, Journal of pharmaceutical sciences.

[16]  Y. Sugiyama,et al.  Gemfibrozil and Its Glucuronide Inhibit the Organic Anion Transporting Polypeptide 2 (OATP2/OATP1B1:SLC21A6)-Mediated Hepatic Uptake and CYP2C8-Mediated Metabolism of Cerivastatin: Analysis of the Mechanism of the Clinically Relevant Drug-Drug Interaction between Cerivastatin and Gemfibrozil , 2004, Journal of Pharmacology and Experimental Therapeutics.

[17]  P. Neuvonen,et al.  Glucuronidation Converts Clopidogrel to a Strong Time‐Dependent Inhibitor of CYP2C8: A Phase II Metabolite as a Perpetrator of Drug–Drug Interactions , 2014, Clinical pharmacology and therapeutics.

[18]  P. Neuvonen,et al.  Cyclosporine markedly raises the plasma concentrations of repaglinide , 2005, Clinical pharmacology and therapeutics.

[19]  T. Goosen,et al.  Mechanistic Modeling to Predict the Transporter- and Enzyme-Mediated Drug-Drug Interactions of Repaglinide , 2013, Pharmaceutical Research.

[20]  Kiyomi Ito,et al.  Effect of buffer conditions on CYP2C8-mediated paclitaxel 6α-hydroxylation and CYP3A4-mediated triazolam α- and 4-hydroxylation by human liver microsomes , 2016, Xenobiotica; the fate of foreign compounds in biological systems.

[21]  I. Bjørnsdottir,et al.  CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide. , 2003, British journal of clinical pharmacology.

[22]  P. Neuvonen,et al.  The cytochrome P4503A4 inhibitor clarithromycin increases the plasma concentrations and effects of repaglinide , 2001, Clinical pharmacology and therapeutics.

[23]  P. Neuvonen,et al.  Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin. , 2005, Basic & clinical pharmacology & toxicology.

[24]  Y. Lai,et al.  Hepatic Disposition of Gemfibrozil and Its Major Metabolite Gemfibrozil 1-O-β-Glucuronide. , 2015, Molecular pharmaceutics.

[25]  Toshihiko Ikeda,et al.  The Quantitative Prediction of CYP-mediated Drug Interaction by Physiologically Based Pharmacokinetic Modeling , 2008, Pharmaceutical Research.

[26]  L Fritsche,et al.  Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine‐treated kidney transplant recipients , 1999, Clinical pharmacology and therapeutics.

[27]  K. Maeda,et al.  Transporter‐Mediated Drug–Drug Interactions Involving OATP Substrates: Predictions Based on In Vitro Inhibition Studies , 2012, Clinical pharmacology and therapeutics.

[28]  A. Galetin,et al.  A Comprehensive Assessment of Repaglinide Metabolic Pathways: Impact of Choice of In Vitro System and Relative Enzyme Contribution to In Vitro Clearance , 2012, Drug Metabolism and Disposition.

[29]  Akihiko Konagaya,et al.  Cluster Newton Method for Sampling Multiple Solutions of Underdetermined Inverse Problems: Application to a Parameter Identification Problem in Pharmacokinetics , 2014, SIAM J. Sci. Comput..

[30]  P. Neuvonen,et al.  Mechanism‐Based Inactivation of CYP2C8 by Gemfibrozil Occurs Rapidly in Humans , 2011, Clinical pharmacology and therapeutics.

[31]  M. Rowland,et al.  Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. , 2006, Journal of pharmaceutical sciences.

[32]  M. Niemi,et al.  Membrane transporters in drug development , 2010, Nature Reviews Drug Discovery.

[33]  Yuichi Sugiyama,et al.  Application of physiologically based pharmacokinetic modeling and clearance concept to drugs showing transporter-mediated distribution and clearance in humans , 2010, Journal of Pharmacokinetics and Pharmacodynamics.

[34]  M Rowland,et al.  Physiologically based pharmacokinetics of cyclosporine A: extension to tissue distribution kinetics in rats and scale-up to human. , 1998, The Journal of pharmacology and experimental therapeutics.

[35]  P. Neuvonen,et al.  The CYP2C8 inhibitor trimethoprim increases the plasma concentrations of repaglinide in healthy subjects. , 2004, British journal of clinical pharmacology.

[36]  Y. Sugiyama,et al.  Analysis of Nonlinear and Nonsteady State Hepatic Extraction with the Dispersion Model Using the Finite Difference Method , 1998, Journal of Pharmacokinetics and Biopharmaceutics.

[37]  K. Maeda,et al.  Quantitative Analyses of Hepatic OATP‐Mediated Interactions Between Statins and Inhibitors Using PBPK Modeling With a Parameter Optimization Method , 2016, Clinical pharmacology and therapeutics.