TACROLIMUS VARIABILITY FACTORS AND INTERPLAY WITH KIDNEY GRAFT FUNCTION

Aleksandra Canevska Taneska; Lada Trajceska; Galina Severova; Irena Rambabova-Bushljetik; Igor Nikolov; Zaklina Shterjova Markovska; Nikola Gjorgjievski; Goce Spasovski

Aleksandra Canevska Taneska University Clinic of Nephrology, Faculty of Medicine Ss.”Cyril and Methodious” University in Skopje, North Macedonia
Lada Trajceska University Clinic of Nephrology, Faculty of Medicine Ss.”Cyril and Methodious” University in Skopje, North Macedonia
Galina Severova University Clinic of Nephrology, Faculty of Medicine Ss.”Cyril and Methodious” University in Skopje, North Macedonia
Irena Rambabova-Bushljetik University Clinic of Nephrology, Faculty of Medicine Ss.”Cyril and Methodious” University in Skopje, North Macedonia
Igor Nikolov University Clinic of Nephrology, Faculty of Medicine Ss.”Cyril and Methodious” University in Skopje, North Macedonia
Zaklina Shterjova Markovska University Clinic of Nephrology, Faculty of Medicine Ss.”Cyril and Methodious” University in Skopje, North Macedonia
Nikola Gjorgjievski University Clinic of Nephrology, Faculty of Medicine Ss.”Cyril and Methodious” University in Skopje, North Macedonia
Goce Spasovski University Clinic of Nephrology, Faculty of Medicine Ss.”Cyril and Methodious” University in Skopje, North Macedonia

Abstract

Introduction: This study aimed to evaluate the association between tacrolimus pharmacokinetic variability and graft function and survival during a one-year follow-up period. Materials and Methods: A prospective study was conducted with 32 kidney transplant patients. Intra-individual variability (CV > 30%) was defined as high. Patients were categorized as slow or fast metabolizers based on the concentration-to-dose ratio (Co/D). The clinical outcome, measured by the change in eGFR, was assessed over a one-year follow-up period. Results: CV > 30% was found in 12.5% of patients, and low Co/D was observed in 15.6%. Both fast metabolizers and patients with high tacrolimus pharmacokinetic variability (IPV) showed higher creatinine levels after 6 and 12 months, along with lower eGFR values. However, these differences did not reach statistical significance (e.g., 135.11 ± 50.89 vs. 158.29 ± 68.33, p = 0.499; 126.36 ± 45.60 vs. 150.80 ± 58.60, p = 0.322). The reduction ratio of eGFR ranged from -64% to +40%, with a mean reduction of -1.26 ± 20.60%. Fast metabolizers did not show a higher frequency of reduction ratios >20% compared to others (3 [15%] vs. 0 [0%], p = 0.585),nor did those with high tacrolimus variability (3 [14.3%] vs. 0 [0%], p = 0.657). In the predictive model, age remained sole significant factor for tacrolimus variability. Conclusion: Further follow-up is needed to fully understand the impact of tacrolimus pharmacokinetic variability on kidney graft function.

Keywords: kidney transplant, tacrolimus, pharmacokinetic variability, graft outcome

References

1.Ying T, Shi B, Kelly PJ, Pilmore H, Clayton PA, Chadban SJ. Death after Kidney Transplantation: An Analysis by Era and Time Post-Transplant. J Am Soc Nephrol. 2020 Dec;31(12):2887-2899
2.Bentata Y. Tacrolimus: 20 years of use in adult kidney transplantation. What we should know about its nephrotoxicity. Artif Organs. 2020 Feb;44(2):140-152
3.Wojciechowski, David; Wiseman, Alexander. Long-Term Immunosuppression Management: Opportunities and Uncertainties. CJASN 16(8):1264-1271, August 2021
4.Park Y, Lee H, Eum SH, Ko EJ, Min JW, Yoon SH et al. Combined impact of the inter and intra-patient variability of tacrolimus blood level on allograft outcomes in kidney transplantation. Front Immunol. 2022 Nov 16;13 :1037566.
5.Mo H, Kim SY, Min S, Han A, Ahn S, Min SK et al. Association of Intrapatient Variability of Tacrolimus ConcentrationWith Early Deterioration of Chronic Histologic Lesions in Kidney Transplantation. Transplant Direct. 2019 May 22;5(6):455.
6.Provenzani A, Santeusanio A, Mathis E, Notarbartolo M, Labbozzetta M, Poma P et al. Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients. World J Gastroenterol. 2013 Dec 28;19(48):9156-73.
7.Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2004;43(10):623–653.
8.Brunet M, Pastor-Anglada M. Insights into the Pharmacogenetics of Tacrolimus Pharmacokinetics and Pharmacodynamics. Pharmaceutics. 2022 Aug 23;14(9):1755
9.Alexandra Degraeve, Serge Moudio , Vincent Haufroid , Djamila Chaib Eddour , Michel Mourad , Laure B Bindels & Laure Elens (2020): Predictors of tacrolimus pharmacokinetic variability: current evidences and future perspectives, Expert Opinion on Drug Metabolism & Toxicology, DOI: 10.1080/17425255.2020.1803277
10.van Gelder T. Drug interactions with tacrolimus. Drug Saf. 2002;25(10):707-12.
11.Kim IW, Moon YJ, Ji E, Kim KI, Han N, Kim SJ et al. Clinical and genetic factors affecting tacrolimus trough levels and drug-related outcomes in Korean kidney transplant recipients. Eur J Clin Pharmacol. 2012 May;68(5):657-69.
12.Thölking G, Fortmann C, Koch R, Gerth HU, Pabst D, Pavenstädt H et al. The tacrolimus metabolism rate influences renal function after kidney transplantation. PLoS One. 2014 Oct 23;9(10):e111128.
13.Katsakiori PF, Papapetrou EP, Goumenos DS, Nikiforidis GC, Flordellis CS. Investigation of clinical interaction between omeprazole and tacrolimus in CYP3A5 non-expressors, renal transplant recipients. Ther Clin Risk Manag. 2010 Jun 24;6: 265-9.
14.Davit BM, Chen ML, Conner DP, Haidar SH, Kim S, Lee CH, et al Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products by the US Food and Drug Administration. AAPS J. 2012 Dec;14(4):915-24.
15.Lada Trajceska et al. Tacrolimus variability in transplantation, Bantao Journal 2019 Vol 17
16.Park Y, Lee H, Eum SH, Ko EJ, Min JW, Yoon SH et al. Combined impact of the inter and intra-patient variability of tacrolimus blood level on allograft outcomes in kidney transplantation. Front Immunol. 2022 Nov 16;13: 1037566
17.Hilbrands L, Budde K, Bellini MI, Diekmann F, Furian L, Grinyó J et al. Allograft Function as Endpoint for Clinical Trials in Kidney Transplantation. Transpl Int. 2022May 20;35:10139.
18.Peng W, Lin Y, Zhang H, Meng K. Effect of ABCB1 3435C>T Genetic Polymorphism on Pharmacokinetic Variables of Tacrolimus in Adult Renal Transplant Recipients: A Systematic Review and Meta-analysis. Clin Ther. 2020 Oct;42(10):2049-2065.
19.Hawwa AF, McKiernan PJ, Shields M, Millership JS, Collier PS, McElnay JC. Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant. Br J Clin Pharmacol. 2009 Sep;68(3):413-21
20.Birdwell KA, Decker B, Barbarino JM, Peterson JF, Stein CM, Sadee W et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther. 2015 Jul;98(1):19-24.
21.European Medicines Agenc. Guideline on the Clinical Investigation of Medicinal Products to Prevent Development/slow Progression of Chronic Renal Insufficiency (2016). Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-medicinal-products-prevent-development/slow-progression-chronic-renal-insufficiency_en.pdf