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

Autor:	Stefanović N; Department of Pharmacy, Faculty of Medicine, University of Nis, 18000 Nis, Serbia., Veličković-Radovanović R; Department of Pharmacology with Toxicology, Faculty of Medicine, University of Nis, 18000 Nis, Serbia.; Clinic of Nephrology, University Clinical Center Nis, 18000 Nis, Serbia., Danković K; Faculty of Medicine, University of Nis, 18000 Nis, Serbia., Pavlović I; Faculty of Mechanical Engineering, University of Nis, 18000 Nis, Serbia., Catić-Đorđević A; Department of Pharmacy, Faculty of Medicine, University of Nis, 18000 Nis, Serbia., Bašić J; Department of Biochemistry, Faculty of Medicine, University of Nis, 18000 Nis, Serbia., Despotović M; Department of Biochemistry, Faculty of Medicine, University of Nis, 18000 Nis, Serbia., Jevtović-Stoimenov T; Department of Biochemistry, Faculty of Medicine, University of Nis, 18000 Nis, Serbia., Mitić B; Clinic of Nephrology, University Clinical Center Nis, 18000 Nis, Serbia.; Department of Internal Medicine, Faculty of Medicine, University of Nis, 18000 Nis, Serbia., Cvetković T; Department of Biochemistry, Faculty of Medicine, University of Nis, 18000 Nis, Serbia.; Center for Clinical and Medical Biochemistry, University Clinical Center Nis, 18000 Nis, Serbia.
Jazyk:	angličtina
Zdroj:	Pharmaceutics [Pharmaceutics] 2021 Nov 20; Vol. 13 (11). Date of Electronic Publication: 2021 Nov 20.
DOI:	10.3390/pharmaceutics13111970
Abstrakt:	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 (C 0 /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 C 0 /D values were derived from CYP3A5 genotype subgroups. Results : Patients characterized by high Tac IPV and low mean C 0 /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 C 0 /D values may suggest its indirect effect on long-term graft function. Conclusion : The findings indicate that simultaneous assessment of Tac IPV, C 0 /D, and CYP3A5 genotype may identify patients at risk of deterioration of graft function in the long-term post-transplantation period.
Databáze:	MEDLINE
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