The effects of the CYP3A5*3 variant on tacrolimus pharmacokinetics and outcomes in Tunisian kidney transplant recipients Section Original articles

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Published Nov 18, 2023
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Vol. 101 No. 10 (2023): Tunis med oct 2023

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Rim charfi
Department of clinical pharmacology, National Centre Chalbi Belkahia of Pharmacovigilance, Research Laboratory of Clinical and Experimental Pharmacology (LR16SP02), Faculty of de Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
Mohamed Mongi Bacha
Department of nephrology and internal medicine, Charles Nicolle hospital -, Research Laboratory of Renal Pathology (LR00SP01), Faculty of de Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisie
Myriam Ben Fadhla
Department of immunology , Charles Nicolle hospital, , Research Laboratory of Immunology of Renal Transplantation and Immunopathology (LR03SP01), Faculty of de Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
Khouloud Ferchichi
Department of clinical pharmacology, National Centre Chalbi Belkahia of Pharmacovigilance, Research Laboratory of Clinical and Experimental Pharmacology (LR16SP02), Faculty of de Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
Hanene El Jebari
Department of clinical pharmacology, National Centre Chalbi Belkahia of Pharmacovigilance, Research Laboratory of Clinical and Experimental Pharmacology (LR16SP02), Faculty of de Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
Emna Gaies
Department of clinical pharmacology, National Centre Chalbi Belkahia of Pharmacovigilance, Research Laboratory of Clinical and Experimental Pharmacology (LR16SP02), Faculty of de Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
Anis Klouz
Department of clinical pharmacology, National Centre Chalbi Belkahia of Pharmacovigilance, Research Laboratory of Clinical and Experimental Pharmacology (LR16SP02), Faculty of de Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
Ezzeddine Abderrahim
Department of nephrology and internal medicine, Charles Nicolle hospital, Research Laboratory of Renal Pathology (LR00SP01), Faculty of de Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
Fathi Ben Hamida
Department of nephrology and internal medicine, Charles Nicolle hospital, Research Laboratory of Renal Pathology (LR00SP01), Faculty of de Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
Taieb Ben Abdallah
Department of nephrology and internal medicine, Charles Nicolle hospital, Research Laboratory of Renal Pathology (LR00SP01), Faculty of de Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
Sameh Trabelsi
Department of clinical pharmacology, National Centre Chalbi Belkahia of Pharmacovigilance, Research Laboratory of Clinical and Experimental Pharmacology (LR16SP02), Faculty of de Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
Yosr Gorgi
Department of immunology, Charles Nicolle hospital, , Research Laboratory of Immunology of Renal Transplantation and Immunopathology (LR03SP01), Faculty of de Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
Imen Sfar
Department of immunology, Charles Nicolle hospital, , Research Laboratory of Immunology of Renal Transplantation and Immunopathology (LR03SP01), Faculty of de Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia

Abstract

Introduction: Tacrolimus, exhibits interindividual pharmacokinetic variability and a narrow therapeutic index. The influence of the CYP3A5 6986A>G single nucleotide polymorphism (SNP) on this variability remains a topic of debate.


Aim: To assess the impact of the aforementioned SNP on tacrolimus area under curve (AUC0-12h), adverse drug reactions (ADRs), and kidney graft outcomes.


Methods: Blood samples were collected from Tunisian kidney transplants over a five-year period during either the early (<3 months) or late (>3 months) post-transplant phases. Through blood concentration (C0) and AUC0-12h of tacrolimus were measured. Patients were prospectively followed to assess graft outcomes. Polymerase chain reaction of restriction fragment length polymorphism was used for CYP3A5 6986A>G genotyping.


Results: Fifty Tunisian kidney recipients receiving tacrolimus were enrolled in the study. Acute and chronic graft rejections were observed in eight and three patients, respectively. Twenty-one patients (42%) reported ADRs. C0 and AUC0-12h, showed a significant difference between CYP3A5*1 carriers (mean C0=4 ng.mL-1 and AUC0-12h=94.37 ng.h.mL-1) and CYP3A5*3/3 or poor metabolizers carriers (mean C0=7.45 ng.mL-1; AUC0-12h=151.27 ng.h.mL-1) (p=0.0001; p=0.003, respectively). Supratherapeutic tacrolimus levels were significantly more common in poor metabolizers (p=0.046; Odds-ratio =1.3; confidence interval 95% [1.12-1.66]). The impact of SNP was significant on C0, AUC0-12h, C0/Dose and AUC0-12h/Dose, only in the late phase (p=0.01, 0.002, 0.012, 0.003 respectively).


Conclusion: Cyp3a5*3 variant was significantly associated with tacrolimus pharmacokinetics but had no impact on graft outcomes.

Keywords:

Adverse drug reaction, kidney grafting, pharmacokinetics, rejection, SNPS, tacrolimus

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Author Biography

Rim charfi, Department of clinical pharmacology, National Centre Chalbi Belkahia of Pharmacovigilance, Research Laboratory of Clinical and Experimental Pharmacology (LR16SP02), Faculty of de Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia

Pharmaco

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