Scientific Publications by FDA Staff

Clin Pharmacol Ther 2019 Mar;105(3):719-29

Use of physiologically-based pharmacokinetic (PBPK) modeling to evaluate the effect of chronic kidney disease on the disposition of hepatic CYP2C8 and OATP1B drug substrates.

Tan ML, Zhao P, Zhang L, Ho YF, Varma MVS, Neuhoff S, Nolin TD, Galetin A, Huang SM

Chronic kidney disease (CKD) differentially affects the pharmacokinetics of nonrenally cleared drugs via certain pathways, e.g., CYP2D6; however, the effect on CYP2C8-mediated clearance is not well understood because of overlapping substrate specificity with hepatic OATPs. This study employed physiologically-based pharmacokinetic (PBPK) modeling to delineate potential changes in CYP2C8 or OATP1B activity in CKD patients. Drugs analyzed are predominantly substrates of CYP2C8 (rosiglitazone, pioglitazone), OATP1B (pitavastatin), or both (repaglinide). Following initial model verification, pharmacokinetics of these drugs were simulated in severe CKD patients considering changes in glomerular filtration rate, 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 CKD patients.