Quantitative Analysis of Complex Drug-Drug Interactions between Cerivastatin and Metabolism/Transport Inhibitors Using Physiologically Based Pharmacokinetic Modeling

Cerivastatin (CER) was withdrawn from the world market because of lethal rhabdomyolysis. Coadministrations of CER and cyclosporine A (CsA) or gemfibrozil (GEM) have been reported to increase the CER blood concentration. CsA is an inhibitor of organic anion transporting polypeptide (OATP)1B1 and CYP3A4, and GEM and its glucuronide (GEM-glu) inhibit OATP1B1 and CYP2C8. The purpose of this study was to describe the transporter-/enzyme-mediated drug-drug interactions (DDIs) of CER with CsA or GEM based on unified physiologically based pharmacokinetic (PBPK) models and to investigate whether the DDIs can be quantitatively analyzed by a bottom-up approach. Initially, the PBPK models for CER and GEM/GEM-glu were constructed based on the previously reported standard protocols. Next, the drug-dependent parameters were optimized by Cluster Newton Method. Thus, described concentration-time profiles for CER and GEM/GEM-glu agreed well with the clinically observed data. The DDIs were then simulated using the established PBPK models with previously obtained in vitro inhibition constants of CsA or GEM/GEM-glu against the OATP1B1 and cytochrome P450s. DDIs with the inhibitors were underestimated compared with observed data using the geometric means of reported values. To search for better described parameters within the range of in vitro values, sensitivity analyses were performed for DDIs of CER. Using the in vitro parameter sets selected by sensitivity analyses, these DDIs were well reproduced, indicating that the present PBPK models were able to describe adequately the clinical DDIs based on a bottom-up approach. The approaches in this study would be applicable to the prediction of other DDIs involving both transporters and metabolic enzymes.

[1]  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.

[2]  K. Maeda,et al.  Substrate-Dependent Inhibition of Organic Anion Transporting Polypeptide 1B1: Comparative Analysis with Prototypical Probe Substrates Estradiol-17β-Glucuronide, Estrone-3-Sulfate, and Sulfobromophthalein , 2013, Drug Metabolism and Disposition.

[3]  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.

[4]  L. Benet,et al.  The Extended Clearance Concept Following Oral and Intravenous Dosing: Theory and Critical Analyses , 2018, Pharmaceutical Research.

[5]  Yuichi Sugiyama,et al.  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. , 2017, Journal of pharmaceutical sciences.

[6]  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..

[7]  Sebastian Polak,et al.  Population-Based Mechanistic Prediction of Oral Drug Absorption , 2009, The AAPS Journal.

[8]  Yoshiyuki Asai,et al.  Integrative and theoretical research on the architecture of a biological system and its disorder , 2019, The Journal of Physiological Sciences.

[9]  A. D. Rodrigues,et al.  GLUCURONIDATION CONVERTS GEMFIBROZIL TO A POTENT, METABOLISM-DEPENDENT INHIBITOR OF CYP2C8: IMPLICATIONS FOR DRUG-DRUG INTERACTIONS , 2006, Drug Metabolism and Disposition.

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

[11]  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.

[12]  Y. Sugiyama,et al.  Method for predicting the risk of drug–drug interactions involving inhibition of intestinal CYP3A4 and P-glycoprotein , 2009, Xenobiotica; the fate of foreign compounds in biological systems.

[13]  E. Wooltorton.  Bayer pulls cerivastatin (Baycol) from market. , 2001, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[14]  U. Hofmann,et al.  Characterisation of cerivastatin as a P-glycoprotein substrate: studies in P-glycoprotein-expressing cell monolayers and mdr1a/b knock-out mice , 2004, Naunyn-Schmiedeberg's Archives of Pharmacology.

[15]  B Agoram,et al.  Predicting the impact of physiological and biochemical processes on oral drug bioavailability. , 2001, Advanced drug delivery reviews.

[16]  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.

[17]  Bertram Pitt,et al.  Withdrawal of cerivastatin from the world market , 2001, Current controlled trials in cardiovascular medicine.

[18]  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.

[19]  Kairui Feng,et al.  The Simcyp® Population-based ADME Simulator , 2009 .

[20]  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.

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

[22]  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.

[23]  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.

[24]  Kairui Feng,et al.  The Simcyp population-based ADME simulator. , 2009, Expert opinion on drug metabolism & toxicology.

[25]  Shelley F. Martin.  Bayer pulls cerivastatin (Baycol) from market. , 2001 .

[26]  K. Ochmann,et al.  Absolute and relative bioavailability of the HMG-CoA reductase inhibitor cerivastatin. , 1997, International journal of clinical pharmacology and therapeutics.

[27]  H. Barton,et al.  Prediction of Pharmacokinetics and Drug–Drug Interactions When Hepatic Transporters are Involved , 2014, Clinical Pharmacokinetics.

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

[29]  W. Mück.  Clinical Pharmacokinetics of Cerivastatin , 2000, Clinical pharmacokinetics.

[30]  Masoud Jamei,et al.  Cytochrome p450 turnover: regulation of synthesis and degradation, methods for determining rates, and implications for the prediction of drug interactions. , 2008, Current drug metabolism.

[31]  M. Radtke,et al.  Biotransformation of cerivastatin in mice, rats, and dogs in vivo. , 1998, Drug metabolism and disposition: the biological fate of chemicals.

[32]  K. Pang,et al.  Why we need proper PBPK models to examine intestine and liver oral drug absorption. , 2012, Current drug metabolism.

[33]  K. Maeda,et al.  Prediction of the Overall Renal Tubular Secretion and Hepatic Clearance of Anionic Drugs and a Renal Drug-Drug Interaction Involving Organic Anion Transporter 3 in Humans by In Vitro Uptake Experiments , 2011, Drug Metabolism and Disposition.

[34]  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.

[35]  Tim Morris,et al.  Physiological Parameters in Laboratory Animals and Humans , 1993, Pharmaceutical Research.

[36]  P. Neuvonen,et al.  Gemfibrozil greatly increases plasma concentrations of cerivastatin , 2002, Clinical pharmacology and therapeutics.

[37]  Yuichi Sugiyama,et al.  Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. , 2006, Pharmacology & therapeutics.

[38]  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.

[39]  K. Maeda,et al.  Comparison of Methods for Estimating Unbound Intracellular-to-Medium Concentration Ratios in Rat and Human Hepatocytes Using Statins , 2017, Drug Metabolism and Disposition.

[40]  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.

[41]  Osamu Okazaki,et al.  Human Pharmacokinetic Prediction of UDP-Glucuronosyltransferase Substrates with an Animal Scale-Up Approach , 2011, Drug Metabolism and Disposition.

[42]  Yuichi Sugiyama,et al.  Inhibition of Transporter-Mediated Hepatic Uptake as a Mechanism for Drug-Drug Interaction between Cerivastatin and Cyclosporin A , 2003, Journal of Pharmacology and Experimental Therapeutics.

[43]  H. Brewer,et al.  Benefit-risk assessment of Rosuvastatin 10 to 40 milligrams. , 2003, The American journal of cardiology.

[44]  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.