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. 2022 Oct 1;44(5):606-614.
doi: 10.1097/FTD.0000000000000979.

Model-Based Tacrolimus Follow-up Dosing in Adult Renal Transplant Recipients: A Simulation Trial

Marith I Francke  1   2   3   4 , Dennis A Hesselink  1   2 , Louise M Andrews  3   5 , Teun van Gelder  6 , Ron J Keizer  7 , Brenda C M de Winter  2   3   4
Affiliations

Model-Based Tacrolimus Follow-up Dosing in Adult Renal Transplant Recipients: A Simulation Trial

Marith I Francke et al. Ther Drug Monit. .

Abstract

Background: Initial algorithm-based dosing appears to be effective in predicting tacrolimus dose requirement. However, achieving and maintaining the target concentrations is challenging. Model-based follow-up dosing, which considers patient characteristics and pharmacological data, may further personalize treatment. This study investigated whether model-based follow-up dosing could lead to more accurate tacrolimus exposure than standard therapeutic drug monitoring (TDM) in kidney transplant recipients after an initial algorithm-based dose.

Methods: This simulation trial included patients from a prospective trial that received an algorithm-based tacrolimus starting dose followed by TDM. For every measured tacrolimus predose concentration (C 0,obs ), model-based dosing advice was simulated using the InsightRX software. Based on previous tacrolimus doses and C 0 , age, body surface area, CYP3A4 and CYP3A5 genotypes, hematocrit, albumin, and creatinine, the optimal next dose, and corresponding tacrolimus concentration (C 0,pred ) were predicted.

Results: Of 190 tacrolimus C 0 values measured in 59 patients, 121 (63.7%; 95% CI 56.8-70.5) C 0,obs were within the therapeutic range (7.5-12.5 ng/mL) versus 126 (66.3%, 95% CI 59.6-73.0) for C 0,pred ( P = 0.89). The median absolute difference between the tacrolimus C 0 and the target tacrolimus concentration (10.0 ng/mL) was 1.9 ng/mL for C 0,obs versus 1.6 ng/mL for C 0,pred . In a historical cohort of 114 kidney transplant recipients who received a body weight-based starting dose followed by TDM, 172 of 335 tacrolimus C 0 (51.3%) were within the therapeutic range (10.0-15.0 ng/mL).

Conclusions: The combination of an algorithm-based tacrolimus starting dose with model-based follow-up dosing has the potential to minimize under- and overexposure to tacrolimus in the early posttransplant phase, although the additional effect of model-based follow-up dosing on initial algorithm-based dosing seems small.

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Conflict of interest statement

D. A. Hesselink has received grant support, paid to his institution, from Astellas Pharma, Chiesi Farmaceutici SpA, and Bristol Myers-Squibb, as well as lecture and consulting fees from Astellas Pharma, Chiesi Farmaceutici SpA, Novartis Pharma, and Vifor Pharma, over the past 3 years. R. J. Keizer is a stockholder and employee of InsightRX, a precision dosing software company. T. van Gelder received lecture fees and study grants from Chiesi and Astellas, in addition to consulting fees from Roche Diagnostics, Thermo Fisher, Vitaeris, CSL Behring, Astellas, and Aurinia Pharma. T. van Gelder neither has employment nor stock ownership at any of these companies, he does not have patents or patent applications. All other authors declare no conflicts of interest.

References

    1. Brunet M, van Gelder T, Åsberg A, et al. Therapeutic drug monitoring of tacrolimus-personalized therapy: second consensus report. Ther Drug Monit. 2019;41:261–307.
    1. Shuker N, Bouamar R, van Schaik RH, et al. A randomized controlled trial comparing the efficacy of Cyp3a5 genotype-based with body-weight-based tacrolimus dosing after living donor kidney transplantation. Am J Transpl. 2016;16:2085–2096.
    1. Thervet E, Loriot MA, Barbier S, et al. Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin Pharmacol Ther. 2010;87:721–726.
    1. Andrews LM, Riva N, de Winter BC, et al. Dosing algorithms for initiation of immunosuppressive drugs in solid organ transplant recipients. Expert Opin Drug Metab Toxicol. 2015;11:921–936.
    1. Passey C, Birnbaum AK, Brundage RC, et al. Dosing equation for tacrolimus using genetic variants and clinical factors. Br J Clin Pharmacol. 2011;72:948–957.