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

<b>Background</b>: Tacrolimus (Tac) is characterized by large between- and within-patient (IPV) variability in pharmacokinetics and exposure. <b>Aim</b>: This study aimed to assess and validate the effect of Tac IPV and trough concentration-to-dose ratio (C<sub>0</su...

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Main Authors: Nikola Stefanović (Author), Radmila Veličković-Radovanović (Author), Katarina Danković (Author), Ivan Pavlović (Author), Aleksandra Catić-Đorđević (Author), Jelena Bašić (Author), Milena Despotović (Author), Tatjana Jevtović-Stoimenov (Author), Branka Mitić (Author), Tatjana Cvetković (Author)
Format: Book
Published: MDPI AG, 2021-11-01T00:00:00Z.
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Summary:<b>Background</b>: Tacrolimus (Tac) is characterized by large between- and within-patient (IPV) variability in pharmacokinetics and exposure. <b>Aim</b>: This study aimed to assess and validate the effect of Tac IPV and trough concentration-to-dose ratio (C<sub>0</sub>/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. <b>Methods</b>: 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<sub>0</sub>/D values were derived from CYP3A5 genotype subgroups. <b>Results</b>: Patients characterized by high Tac IPV and low mean C<sub>0</sub>/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<sub>0</sub>/D values may suggest its indirect effect on long-term graft function. <b>Conclusion</b>: The findings indicate that simultaneous assessment of Tac IPV, C<sub>0</sub>/D, and CYP3A5 genotype may identify patients at risk of deterioration of graft function in the long-term post-transplantation period.
Item Description:10.3390/pharmaceutics13111970
1999-4923

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