Effect of the Interrelation between CYP3A5 Genotype, Concentration/Dose Ratio and Intrapatient Variability of Tacrolimus on Kidney Graft Function: Monte Carlo Simulation Approach

Abstract

Background: Tacrolimus (Tac) is characterized by large between- and within-patient (IPV) variability in pharmacokinetics and exposure. Aim: This study aimed to assess and validate the effect of Tac IPV and trough concentration-to-dose ratio (C0/D) over 6–12 months on reduced estimated glomerular filtration rate (eGFR) values in the late period after kidney transplantation (Tx), applying Monte Carlo (MC) simulation. Methods: The previously published linear regression was the basis for MC simulation, performed to determine how variations in significant predictors affect the distribution of eGFR from 13 to 36 months post-transplantation. The input C0/D values were derived from CYP3A5 genotype subgroups. Results: Patients characterized by high Tac IPV and low mean C0/D over 6–12 months could have been at greater risk of lower eGFR values in a three-year period following Tx compared to the other patient groups. This effect was more pronounced in patients with a lower eGFR at the 6th month and a history of acute rejection. The proven contribution of CYP3A5 expresser genotype to low C0/D values may suggest its indirect effect on long-term graft function. Conclusion: The findings indicate that simultaneous assessment of Tac IPV, C0/D, and CYP3A5 genotype may identify patients at risk of deterioration of graft function in the long-term post-transplantation period.

Can Pre-Transplant Psychometric Testing Predict Tacrolimus Intrapatient Variability After Living Kidney Transplantation?

“…The worse renal function observed for the H-IPV 30 group compared with the L-IPV 30 group one year after transplantation concurs with recent reports of Tac IPV greater than 30% and kidney graft function [ 23 , 30 , 31 ]. Two methods have been used to determine the cutoff value for Tac IPV in previous studies, and these include the median value of the study population and a value of 30 [ 23 , 30 , 32 , 33 ].…”

Tacrolimus—why pharmacokinetics matter in the clinic

“…Therefore, a correlation of CYP3A5*1 with a low C/D ratio has been expected. Recent studies gained evidence of this assumption and found a strong association of CYP3A5 genotype with a low C/D ratio and a decline in eGFR values ( 60 , 169 , 170 ).…”