Effect of the interrelation between CYP3A5 genotype, concentration/dose ratio and intrapatient variability of tacrolimus on kidney graft function: Monte carlo simulation approach

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.