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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 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.
Pubmed ID: 30074626
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Research based company providing predictive pharmacokinetic and pharmacodynamic tools, workshops and consultancy services. Their user-friendly simulator and databases predict drug absorption, clearance, distribution and metabolic drug-drug interactions from in vitro data. Simcyp's clients include major global pharmaceutical and bioscience companies, leading academic institutes and regulatory authorities. These clients form the Simcyp Consortium, which together with independent International Scientific Advisory Board, guide scientific development at Simcyp.Simcyp was acquired by Certara in 2012.
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