Precision Dosing for Tacrolimus Using Genotypes and Clinical Factors in Kidney Transplant Recipients of European Ancestry

Abstract

Genetic variation in the CYP3A4 and CYP3A5 (CYP3A4/5) genes, which encode the key enzymes in tacrolimus metabolism, is associated with tacrolimus clearance and dose requirements. Tacrolimus has a narrow therapeutic index with high intra‐ and intersubject variability, in part because of genetic variation. High tacrolimus clearance and low trough concentration are associated with a greater risk for rejection, whereas high troughs are associated with calcineurin‐induced toxicity. The objective of this study was to develop a model of tacrolimus clearance with a dosing equation accounting for genotypes and clinical factors in adult kidney transplant recipients of European ancestry that could preemptively guide dosing. Recipients receiving immediate‐release tacrolimus for maintenance immunosuppression from 2 multicenter studies were included. Participants in the GEN03 study were used for tacrolimus model development (n = 608 recipients) and was validated by prediction performance in the DeKAF Genomics study (n = 1361 recipients). Nonlinear mixed‐effects modeling was used to develop the apparent oral tacrolimus clearance (CL/F) model. CYP3A4/5 genotypes and clinical covariates were tested for their influence on CL/F. The predictive performance of the model was determined by assessing the bias (median prediction error [ME] and median percentage error [MPE]) and the precision (root median squared error [RMSE]) of the model. CYP3A5*3, CYP3A4*22, corticosteroids, calcium channel blocker and antiviral drug use, age, and diabetes significantly contributed to the interindividual variability of oral tacrolimus apparent clearance. The bias (ME, MPE) and precision (RMSE) of the final model was good, 0.49 ng/mL, 6.5%, and 3.09 ng/mL, respectively. Prospective testing of this equation is warranted.

Impact of CYP3A5 genotype on de-novo LCP tacrolimus dosing and monitoring in kidney transplantation

“…The landmark, NIH-funded, multicenter DEKAF study provides significant information regarding CYP3A5 genotypes and IR tac dosing requirements. This was an observational study in 1969 patients, which determined that *1/*1 and *1/*3 expressors had a 305 and 181% increase in oral IR tac clearance compared with *3/*3 individuals [11]. In additional DEKAF work, Sanghavi et al .…”

“…Due to its high PK variability profile, tac is universally monitored using whole blood trough concentrations [7][8][9][10][11]. As an orally administered medication, tac is absorbed through the gut and is metabolized via CYP3A4/5 that catalyze its conversion to various inactive O-demethylated metabolites [11,12]. Tac is also a substrate for P-glycoprotein, which is involved in the efflux of multiple drugs [13].…”

“…Tac is also a substrate for P-glycoprotein, which is involved in the efflux of multiple drugs [13]. There are two primary CYP enzymes, CYP 3A4 and CYP3A5, with the 3A5 variant contributing more towards the metabolism of tac [11,12]. Up to 45% of the variability in dose requirements of tac can be explained by CYP3A5 polymorphisms [14].…”

Current status of glucocorticoid usage in solid organ transplantation

“…Interactions between GCs and tacrolimus are more seen in patients carrying the CYP3A5*1 allele[ 133 ]. GCs significantly contribute to inter-individual variability of apparent clearance of oral tacrolimus[ 134 ]. On the other hand, some studies reported that cyclosporine decreases prednisolone clearance by 25%-30% in kidney transplant patients[ 135 ], while others found no difference in dose-adjusted exposure of prednisolone when co-administered with cyclosporine or tacrolimus[ 136 ].…”

Current Status of Glucocorticoid Usage in Solid Organ Transplantation

“…Interactions between GCs and tacrolimus are more seen in patients carrying CYP3A5*1 allele [133] . GCs significantly contributes to inter-individual variability of apparent clearance of oral tacrolimus [134] . On the other hand, some studies reported that cyclosporine decreases prednisolone clearance by 25-30% in kidney transplant patients [135] , while others found no difference in dose-adjusted exposure of prednisolone when co-administered with cyclosporine or tacrolimus [136] .…”