Use of Physiologically Based Pharmacokinetic Modeling to Evaluate the Effect of Chronic Kidney Disease on the Disposition of Hepatic CYP2C8 and OATP1B Drug Substrates
Journal
Clinical Pharmacology and Therapeutics
Journal Volume
105
Journal Issue
3
Pages
719-729
Date Issued
2019
Author(s)
Abstract
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. 2018 The Authors. Clinical Pharmacology and Therapeutics published by Wiley Periodicals, Inc on behalf of the American Society for Clinical Pharmacology and Therapeutics
SDGs
Other Subjects
cyclosporine; cytochrome P450 2C8; gemfibrozil; glucuronide; organic anion transporter; pioglitazone; pitavastatin; repaglinide; rosiglitazone; solute carrier organic anion transporter 1B; solute carrier organic anion transporter 1B1; unclassified drug; antidiabetic agent; CYP2C8 protein, human; cytochrome P450 2C8; hydroxymethylglutaryl coenzyme A reductase inhibitor; SLCO1B1 protein, human; adult; area under the curve ratio; Article; biliary excretion; blood-to-plasma ratio; chronic kidney failure; controlled study; drug analysis; drug clearance; drug distribution; drug elimination; drug interaction; drug metabolism; enzyme specificity; female; glomerulus filtration rate; human; major clinical study; male; pharmacogenetic testing; pharmacokinetic parameters; pharmacokinetics; plasma concentration-time curve; plasma protein binding; sensitivity analysis; simulation; aged; biological model; chronic kidney failure; drug effect; liver; metabolic clearance rate; metabolism; middle aged; physiology; tissue distribution; Adult; Aged; Cytochrome P-450 CYP2C8; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Liver; Liver-Specific Organic Anion Transporter 1; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Renal Insufficiency, Chronic; Tissue Distribution
Type
journal article