Use of Physiologically Based Pharmacokinetic Modeling to Evaluate the Effect of Chronic Kidney Disease on the Disposition of Hepatic CYP2C8 and OATP1B Drug Substrates

Chronic kidney disease (CKD) differentially affects the pharmacokinetics (PK) of nonrenally cleared drugs via certain pathways (e.g., cytochrome P450 (CYP)2D6); however, the effect on CYP2C8‐mediated clearance is not well understood because of overlapping substrate specificity with hepatic organic anion‐transporting polypeptides (OATPs). This study used physiologically based pharmacokinetic (PBPK) modeling to delineate potential changes in CYP2C8 or OATP1B activity in patients with CKD. Drugs analyzed are predominantly substrates of CYP2C8 (rosiglitazone and pioglitazone), OATP1B (pitavastatin), or both (repaglinide). Following initial model verification, pharmacokinetics (PK) of these drugs were simulated in patients with severe CKD considering changes in glomerular filtration rate (GFR), plasma protein binding, and activity of either CYP2C8 and/or OATP1B in a stepwise manner. The PBPK analysis suggests that OATP1B activity could be decreased up to 60% in severe CKD, whereas changes to CYP2C8 are negligible. This improved understanding of CKD effect on clearance pathways could be important to inform the optimal use of nonrenally eliminated drugs in patients with CKD.

[1]  Shiew-Mei Huang,et al.  Effect of Chronic Kidney Disease on Nonrenal Elimination Pathways: A Systematic Assessment of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and OATP , 2017, Clinical pharmacology and therapeutics.

[2]  D. Weiner,et al.  Public Health Consequences of Chronic Kidney Disease , 2009, Clinical pharmacology and therapeutics.

[3]  T. Nolin,et al.  ESRD impairs nonrenal clearance of fexofenadine but not midazolam. , 2009, Journal of the American Society of Nephrology : JASN.

[4]  Malcolm Rowland,et al.  Cyclosporine Inhibition of Hepatic and Intestinal CYP3A4, Uptake and Efflux Transporters: Application of PBPK Modeling in the Assessment of Drug-Drug Interaction Potential , 2012, Pharmaceutical Research.

[5]  A. Galetin,et al.  Delineating the Role of Various Factors in Renal Disposition of Digoxin through Application of Physiologically Based Kidney Model to Renal Impairment Populations , 2017, The Journal of Pharmacology and Experimental Therapeutics.

[6]  P. Neuvonen,et al.  Dose-Dependent Interaction between Gemfibrozil and Repaglinide in Humans: Strong Inhibition of CYP2C8 with Subtherapeutic Gemfibrozil Doses , 2011, Drug Metabolism and Disposition.

[7]  C. Aquilante,et al.  Impact of the CYP2C8 *3 polymorphism on the drug-drug interaction between gemfibrozil and pioglitazone. , 2013, British journal of clinical pharmacology.

[8]  Jonathan Himmelfarb,et al.  Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport , 2013, Kidney international.

[9]  M Rowland,et al.  Best Practice in the Use of Physiologically Based Pharmacokinetic Modeling and Simulation to Address Clinical Pharmacology Regulatory Questions , 2012, Clinical pharmacology and therapeutics.

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

[11]  Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with decreased renal function , 2016 .

[12]  T. Nolin,et al.  Hemodialysis acutely improves hepatic CYP3A4 metabolic activity. , 2006, Journal of the American Society of Nephrology : JASN.

[13]  M. Niemi,et al.  Effects of Gemfibrozil and Atorvastatin on the Pharmacokinetics of Repaglinide in Relation to SLCO1B1 Polymorphism , 2008, Clinical pharmacology and therapeutics.

[14]  K. Maeda,et al.  Involvement of BCRP (ABCG2) in the Biliary Excretion of Pitavastatin , 2005, Molecular Pharmacology.

[15]  Shiew-Mei Huang,et al.  Physiologically Based Pharmacokinetic Modeling of Drug Transporters to Facilitate Individualized Dose Prediction. , 2017, Journal of pharmaceutical sciences.

[16]  J. Samet,et al.  Food and Drug Administration , 2007, BMJ : British Medical Journal.

[17]  Ken Grime,et al.  Species Differences in Biliary Clearance and Possible Relevance of Hepatic Uptake and Efflux Transporters Involvement , 2013, Drug Metabolism and Disposition.

[18]  Jingjing Yu,et al.  Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification , 2015, Drug Metabolism and Disposition.

[19]  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.

[20]  Hugh A. Barton,et al.  Mechanistic Pharmacokinetic Modeling for the Prediction of Transporter-Mediated Disposition in Humans from Sandwich Culture Human Hepatocyte Data , 2012, Drug Metabolism and Disposition.

[21]  David Hung-Tsang Yen,et al.  Risk factors associated with adverse drug events among older adults in emergency department. , 2014, European journal of internal medicine.

[22]  S. Oliver,et al.  Bioavailability of repaglinide, a novel antidiabetic agent, administered orally in tablet or solution form or intravenously in healthy male volunteers. , 1998, International journal of clinical pharmacology and therapeutics.

[23]  Shiew-Mei Huang,et al.  Evaluation of Exposure Change of Nonrenally Eliminated Drugs in Patients With Chronic Kidney Disease Using Physiologically Based Pharmacokinetic Modeling and Simulation , 2012, Journal of clinical pharmacology.

[24]  K. Maeda,et al.  SLCO1B1 (OATP1B1, an Uptake Transporter) and ABCG2 (BCRP, an Efflux Transporter) Variant Alleles and Pharmacokinetics of Pitavastatin in Healthy Volunteers , 2007, Clinical pharmacology and therapeutics.

[25]  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.

[26]  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.

[27]  L Zhang,et al.  Applications of Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation During Regulatory Review , 2011, Clinical pharmacology and therapeutics.

[28]  Nikolaos Tsamandouras,et al.  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 , 2014, Pharmaceutical Research.

[29]  A. Rostami-Hodjegan,et al.  Physiologically Based Pharmacokinetics Joined With In Vitro–In Vivo Extrapolation of ADME: A Marriage Under the Arch of Systems Pharmacology , 2012, Clinical pharmacology and therapeutics.

[30]  M. Jamei,et al.  Modeling and predicting drug pharmacokinetics in patients with renal impairment , 2011, Expert review of clinical pharmacology.

[31]  T. Nolin,et al.  Emerging Evidence of the Impact of Kidney Disease on Drug Metabolism and Transport , 2008, Clinical pharmacology and therapeutics.

[32]  Ann K. Miller,et al.  Pharmacokinetics of Rosiglitazone in Patients with Varying Degrees of Renal Insufficiency , 2003, Journal of clinical pharmacology.

[33]  R. Vanholder,et al.  Uremic toxins inhibit renal metabolic capacity through interference with glucuronidation and mitochondrial respiration. , 2013, Biochimica et biophysica acta.

[34]  Christine Y. Yu,et al.  Comparison of the Safety, Tolerability, and Pharmacokinetic Profile of a Single Oral Dose of Pitavastatin 4 mg in Adult Subjects With Severe Renal Impairment Not on Hemodialysis Versus Healthy Adult Subjects , 2012, Journal of cardiovascular pharmacology.

[35]  T. Marbury,et al.  Pharmacokinetics of repaglinide in subjects with renal impairment , 2000, Clinical pharmacology and therapeutics.

[36]  Ann K. Miller,et al.  Absorption, disposition, and metabolism of rosiglitazone, a potent thiazolidinedione insulin sensitizer, in humans. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[37]  A. Rowland,et al.  Inhibition of human drug-metabolising cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in vitro by uremic toxins , 2014, European Journal of Clinical Pharmacology.

[38]  N. Nakamichi,et al.  Direct Inhibition and Down-regulation by Uremic Plasma Components of Hepatic Uptake Transporter for SN-38, an Active Metabolite of Irinotecan, in Humans , 2013, Pharmaceutical Research.

[39]  Lei Zhang,et al.  Towards Quantitation of the Effects of Renal Impairment and Probenecid Inhibition on Kidney Uptake and Efflux Transporters, Using Physiologically Based Pharmacokinetic Modelling and Simulations , 2014, Clinical Pharmacokinetics.

[40]  Prajakti A Kothare,et al.  Pitavastatin is a more sensitive and selective organic anion-transporting polypeptide 1B clinical probe than rosuvastatin. , 2014, British journal of clinical pharmacology.

[41]  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.

[42]  K. Giacomini,et al.  PBPK Modeling of the Effect of Reduced Kidney Function on the Pharmacokinetics of Drugs Excreted Renally by Organic Anion Transporters , 2018, Clinical pharmacology and therapeutics.

[43]  I. Zineh,et al.  Systematic and quantitative assessment of the effect of chronic kidney disease on CYP2D6 and CYP3A4/5 , 2016, Clinical pharmacology and therapeutics.

[44]  Lei Zhang,et al.  Physiologically Based Pharmacokinetic (PBPK) Modeling of Pitavastatin and Atorvastatin to Predict Drug-Drug Interactions (DDIs) , 2016, European Journal of Drug Metabolism and Pharmacokinetics.

[45]  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.

[46]  D. Eckland,et al.  The pharmacokinetics of pioglitazone in patients with impaired renal function. , 2003, British journal of clinical pharmacology.

[47]  P. Artursson,et al.  Mechanistic Modeling of Pitavastatin Disposition in Sandwich-Cultured Human Hepatocytes: A Proteomics-Informed Bottom-Up Approach , 2016, Drug Metabolism and Disposition.

[48]  I Zineh,et al.  PBPK Model Describes the Effects of Comedication and Genetic Polymorphism on Systemic Exposure of Drugs That Undergo Multiple Clearance Pathways , 2014, Clinical pharmacology and therapeutics.

[49]  K. Maeda,et al.  Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the Hepatic Uptake of Pitavastatin in Humans , 2004, Journal of Pharmacology and Experimental Therapeutics.

[50]  K. Maeda,et al.  DRUG-DRUG INTERACTION BETWEEN PITAVASTATIN AND VARIOUS DRUGS VIA OATP1B1 , 2006, Drug Metabolism and Disposition.

[51]  B. Feng,et al.  Physiologically Based Modeling of Pravastatin Transporter-Mediated Hepatobiliary Disposition and Drug-Drug Interactions , 2012, Pharmaceutical Research.