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Title: Use of Physiologically Based Pharmacokinetic Modeling to Evaluate the Effect of Chronic Kidney Disease on the Disposition of Hepatic CYP 2C8 and OATP 1B Drug Substrates

Journal Article · · Clinical Pharmacology and Therapeutics
DOI: https://doi.org/10.1002/cpt.1205 · OSTI ID:1479504
 [1];  [2];  [3];  [4];  [5];  [6]; ORCiD logo [7];  [8];  [1]
  1. Office of Clinical Pharmacology Office of Translational Sciences Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring Maryland USA
  2. Office of Clinical Pharmacology Office of Translational Sciences Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring Maryland USA, Quantitative Sciences Global Health‐Integrated Development Bill and Melinda Gates Foundation Seattle Washington USA
  3. Office of Clinical Pharmacology Office of Translational Sciences Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring Maryland USA, Office of Research and Standards Office of Generic Drugs Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring Maryland USA
  4. Graduate Institute of Clinical Pharmacy College of Medicine National Taiwan University Taipei Taiwan
  5. Pharmacokinetics, Pharmacodynamics &, Metabolism Department‐New Chemical Entities Pfizer Inc. Groton Connecticut USA
  6. Simcyp Division Certara UK Ltd. Sheffield UK
  7. Center for Clinical Pharmaceutical Sciences Department of Pharmacy and Therapeutics, and Department of Medicine Renal‐Electrolyte Division Schools of Pharmacy and Medicine University of Pittsburgh Pittsburgh Pennsylvania USA
  8. Centre for Applied Pharmacokinetic Research School of Heath Sciences University of Manchester Manchester UK
+ Show Author Affiliations

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 CYP 2C8‐mediated clearance is not well understood because of overlapping substrate specificity with hepatic organic anion‐transporting polypeptides ( OATP s). This study used physiologically based pharmacokinetic ( PBPK ) modeling to delineate potential changes in CYP 2C8 or OATP 1B activity in patients with CKD . Drugs analyzed are predominantly substrates of CYP 2C8 (rosiglitazone and pioglitazone), OATP 1B (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 CYP 2C8 and/or OATP 1B in a stepwise manner. The PBPK analysis suggests that OATP 1B activity could be decreased up to 60% in severe CKD , whereas changes to CYP 2C8 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 .

Research Organization:
Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
Sponsoring Organization:
National Institutes of Health (NIH); U.S. Food and Drug Administration (FDA); USDOE; USDOE Office of Science (SC)
Grant/Contract Number:
SC0014664
OSTI ID:
1479504
Journal Information:
Clinical Pharmacology and Therapeutics, Journal Name: Clinical Pharmacology and Therapeutics Journal Issue: 3 Vol. 105; ISSN 0009-9236
Publisher:
Wiley-BlackwellCopyright Statement
Country of Publication:
United States
Language:
English

References (47)

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PBPK Modeling of the Effect of Reduced Kidney Function on the Pharmacokinetics of Drugs Excreted Renally by Organic Anion Transporters journal July 2017
Effect of Chronic Kidney Disease on Nonrenal Elimination Pathways: A Systematic Assessment of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and OATP journal October 2017
Physiologically based pharmacokinetic modelling 2: Predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions journal June 2006
Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide journal February 2003
Inhibition of human drug-metabolising cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in vitro by uremic toxins journal June 2014
Physiologically Based Modeling of Pravastatin Transporter-Mediated Hepatobiliary Disposition and Drug-Drug Interactions journal May 2012
Cyclosporine Inhibition of Hepatic and Intestinal CYP3A4, Uptake and Efflux Transporters: Application of PBPK Modeling in the Assessment of Drug-Drug Interaction Potential journal November 2012
Mechanistic Modeling to Predict the Transporter- and Enzyme-Mediated Drug-Drug Interactions of Repaglinide journal January 2013
Direct Inhibition and Down-regulation by Uremic Plasma Components of Hepatic Uptake Transporter for SN-38, an Active Metabolite of Irinotecan, in Humans journal August 2013
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 journal March 2014
Physiologically Based Pharmacokinetic (PBPK) Modeling of Pitavastatin and Atorvastatin to Predict Drug-Drug Interactions (DDIs) journal November 2016
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PBPK Model Describes the Effects of Comedication and Genetic Polymorphism on Systemic Exposure of Drugs That Undergo Multiple Clearance Pathways journal February 2014
Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport journal March 2014
SLCO1B1 (OATP1B1, an Uptake Transporter) and ABCG2 (BCRP, an Efflux Transporter) Variant Alleles and Pharmacokinetics of Pitavastatin in Healthy Volunteers journal April 2007
The pharmacokinetics of pioglitazone in patients with impaired renal function: Pioglitazone pharmacokinetics in renally impaired patients journal April 2003
Pharmacokinetics of repaglinide in subjects with renal impairment journal January 2000
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 journal January 2012
Pitavastatin is a more sensitive and selective organic anion-transporting polypeptide 1B clinical probe than rosuvastatin: Drug interaction studies between rifampicin and pitavastatin or rosuvastatin journal August 2014
Impact of the CYP2C8 * 3 polymorphism on the drug-drug interaction between gemfibrozil and pioglitazone journal December 2012
Drug-Drug Interaction Between Pitavastatin and Various Drugs via Oatp1b1 journal April 2006
Dose-Dependent Interaction between Gemfibrozil and Repaglinide in Humans: Strong Inhibition of CYP2C8 with Subtherapeutic Gemfibrozil Doses journal July 2011
Mechanistic Pharmacokinetic Modeling for the Prediction of Transporter-Mediated Disposition in Humans from Sandwich Culture Human Hepatocyte Data journal February 2012
A Comprehensive Assessment of Repaglinide Metabolic Pathways: Impact of Choice of In Vitro System and Relative Enzyme Contribution to In Vitro Clearance journal March 2012
Species Differences in Biliary Clearance and Possible Relevance of Hepatic Uptake and Efflux Transporters Involvement journal November 2012
Quantitative Rationalization of Gemfibrozil Drug Interactions: Consideration of Transporters-Enzyme Interplay and the Role of Circulating Metabolite Gemfibrozil 1- O - β -Glucuronide journal May 2015
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Mechanistic Modeling of Pitavastatin Disposition in Sandwich-Cultured Human Hepatocytes: A Proteomics-Informed Bottom-Up Approach journal February 2016
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 journal July 2016
Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the Hepatic Uptake of Pitavastatin in Humans journal May 2004
Delineating the Role of Various Factors in Renal Disposition of Digoxin through Application of Physiologically Based Kidney Model to Renal Impairment Populations journal January 2017
Involvement of BCRP (ABCG2) in the Biliary Excretion of Pitavastatin journal June 2005
Pharmacokinetics of Rosiglitazone in Patients with Varying Degrees of Renal Insufficiency journal March 2003
Evaluation of Exposure Change of Nonrenally Eliminated Drugs in Patients With Chronic Kidney Disease Using Physiologically Based Pharmacokinetic Modeling and Simulation journal January 2012
Modeling and predicting drug pharmacokinetics in patients with renal impairment journal March 2011
Hemodialysis Acutely Improves Hepatic CYP3A4 Metabolic Activity journal August 2006
ESRD Impairs Nonrenal Clearance of Fexofenadine but not Midazolam journal August 2009

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