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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
Author(s) -
Tan MingLiang,
Zhao Ping,
Zhang Lei,
Ho YunnFang,
Varma Manthena V.S.,
Neuhoff Sibylle,
Nolin Thomas D.,
Galetin Aleksandra,
Huang ShiewMei
Publication year - 2019
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1205
Subject(s) - physiologically based pharmacokinetic modelling , pharmacokinetics , pharmacology , organic anion transporting polypeptide , chemistry , repaglinide , cyp2c8 , renal function , drug , cyp2c9 , cytochrome p450 , medicine , endocrinology , transporter , biochemistry , metabolism , diabetes mellitus , type 2 diabetes , gene
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 .