Systematic and quantitative assessment of the effect of chronic kidney disease on CYP2D6 and CYP3A4/5

Abstract

Recent reviews suggest that chronic kidney disease (CKD) can affect the pharmacokinetics of nonrenally eliminated drugs, but the impact of CKD on individual elimination pathways has not been systematically evaluated. In this study we developed a comprehensive dataset of the effect of CKD on the pharmacokinetics of CYP2D6- and CYP3A4/5-metabolized drugs. Drugs for evaluation were selected based on clinical drug-drug interaction (CYP3A4/5 and CYP2D6) and pharmacogenetic (CYP2D6) studies. Information from dedicated CKD studies was available for 13 and 18 of the CYP2D6 and CYP3A4/5 model drugs, respectively. Analysis of these data suggested that CYP2D6-mediated clearance is generally decreased in parallel with the severity of CKD. There was no apparent relationship between the severity of CKD and CYP3A4/5-mediated clearance. The observed elimination-route dependency in CKD effects between CYP2D6 and CYP3A4/5 may inform the need to conduct clinical CKD studies with nonrenally eliminated drugs for optimal use of drugs in patients with CKD.

Figure 1

Overview of the workflow of clinical CKD data collection for CYP2D6 and CYP3A4/5 model drugs. AUCR, area under the concentration‐time curve ratio; AUCR_liver, AUCR attributable to the inhibition of hepatic CYP3A4/5; CKD, chronic kidney disease; CYP, cytochrome P450; DDI, drug‐drug interaction; DIDB, The University of Washington Metabolism and Transport Drug Interaction Database; PK, pharmacokinetics; USFDA, United States Food and Drug Administration.

Figure 2

Effect of CKD on (a,c) CYP2D6 and (b,d) CYP3A4/5 model drugs. Symbols represent (a,b) R_CL_unbound in each CKD group of a clinical CKD study for drugs with unbound fraction information in healthy control and CKD groups, or (c,d) R_CL_total for drugs without unbound fraction information in CKD studies. CKD, chronic kidney disease; CYP, cytochrome P450; ESRD, endstage renal disease; R_CL_unbound, ratio of clearance between CKD groups and the healthy control group; R_CL_unbound, ratio of unbound clearance between CKD groups and the healthy control group; R_CL_total, ratio of clearance calculated with total (bound plus unbound) concentration between CKD groups and the healthy control group.

Figure 3

Comparison of observed R_CL and theoretical lowest R_CL without changes in nonrenal clearance for (a,c) CYP2D6 and (b,d) CYP3A4/5 model drugs, and (e) graphical representation of the calculation method of theoretical lowest R_CL. The black box and whisker represent interquartile range of (a,b) R_CL_unbound for drugs with unbound fraction information, or (c,d) R_CL_total for all drugs with CKD studies. “+” symbol represents mean value of R_CL, and the orange lines represent the theoretical lowest R_CL assuming no changes in nonrenal clearance (as shown in (e); the values are 0.88, 0.79, 0.73, and 0.69 for the mild, moderate, severe, and the ESRD groups, respectively). CKD, chronic kidney disease; CYP, cytochrome P450; ESRD, endstage renal disease; n, number of CKD studies in each category; R_CL_unbound, ratio of clearance between CKD groups and the healthy control group; R_CL_unbound, ratio of unbound clearance between CKD groups and the healthy control group; R_CL_total, ratio of clearance calculated with total (bound plus unbound) concentration between CKD groups and the healthy control group.

Figure 4

Effect of CKD on (a,c) CYP2D6 and (b,d) CYP3A4/5 mediated clearance. The black box and whisker represent interquartile range of (a,b) unbound R_CL_CYP for drugs with unbound fraction information, or (b,d) R_CL_CYP calculated with total (bound plus unbound) concentration for all drugs with CKD studies. “+” symbol represents mean value of R_CL. CKD, chronic kidney disease; CYP, cytochrome P450; ESRD, endstage renal disease; R_CL_CYP, ratio of clearance mediated by CYP2D6 or CYP3A4/5 between CKD groups and the healthy control group.