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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 .

clinical pharmacology and therapeutics

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