Use of Physiologically Based Pharmacokinetic Modeling to Evaluate the Effect of Chronic Kidney Disease on the Disposition of Hepatic CYP2C8 and OATP1B Drug Substrates

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.

Effect of Hepatic Organic Anion‐Transporting Polypeptide 1B Inhibition and Chronic Kidney Disease on the Pharmacokinetics of a Liver‐Targeted Glucokinase Activator: A Model‐Based Evaluation

“…Subsequent evaluation of PKs in renal impairment subjects suggests ~ 35% reduction in OATP1B function in moderate and severe renal impairment. These findings are in agreement with a recent report indicating about 40% reduction in OATP activity better describe oral clearance of pitavastatin in severe kidney disease . Oxidative metabolism of PF‐04991532 was thought to involve CYP3A (major biotransformation pathway), although its contribution to hepatic clearance is predicted to be low.…”

“…These findings are in agreement with a recent report indicating about 40% reduction in OATP activity better describe oral clearance of pitavastatin in severe kidney disease. 30 Oxidative metabolism of PF-04991532 was thought to involve CYP3A (major biotransformation pathway), 20 although its contribution to hepatic clearance is predicted to be low. However, clinical PKs of CYP3A probe substrates seem to be unaltered in kidney dysfunction.…”

“…Due to lack of protein abundance data in the renal impaired population, expression of transporters in OATP1B1, BCRP, and OAT3 is assumed to be similar to that of healthy volunteers in these default models—which limits “bottom‐up” predictions. Therefore, a “middle‐out” approach, similar to that described recently, was adopted to describe PKs in moderate and severe renal impairment subjects. Here, functional activity of OATP1B1 and OAT3 are decreased to simultaneously recover the plasma concentration‐time profiles, as well as % dose excreted in urine, observed in moderate and severe renal impairment subjects.…”

Physiologically Based Pharmacokinetic Modeling in Regulatory Science: An Update From the U.S. Food and Drug Administration’s Office of Clinical Pharmacology

“…For example, the effect of chronic kidney disease on key physiological model parameters (such as enzyme/transporter activity/abundance) is considered underdeveloped to provide reliable PBPK prediction, particularly for the severe renal impairment population, at this time. [30][31][32][33][34] Engaging With FDA Regarding PBPK-Related Submissions Early communication with the OCP is highly encouraged to promote discussions on modeling strategy, areas of uncertainty, and the types of supporting evidence needed for model development, verification, and application. Given the complexity of these models, early engagement between the sponsors and the OCP also provides the reviewers an opportunity to orient themselves to the modeling strategy that may potentially reduce the number of information requests by the OCP review team if the model is ultimately included in an NDA/BLA submission.…”

Novel Mechanistic PBPK Model to Predict Renal Clearance in Varying Stages of CKD by Incorporating Tubular Adaptation and Dynamic Passive Reabsorption

“…PBPK modeling has been proposed as a promising tool to predict drug disposition in complicated and unknown scenarios, including patients with renal impairment, [32][33][34][35][36] due to its mechanistic capability of integrating multiple complex interactions. Indeed, progress has been made in PBPK modeling of CKD effects on drug disposition, with special attention focused on altered hepatic metabolism 35,[37][38][39] and renal active secretion.…”