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The CYP3A4*22 Allelic Variant Increases the Risk of Tacrolimus Overexposure in Kidney Transplant Recipients.

2014; Wolters Kluwer; Volume: 98; Linguagem: Inglês

10.1097/00007890-201407151-02292

1534-6080

Patrick Nicolas, E. Manele, E. Isebelle, Barbara J. Mathias, C. Gabriel, T. Sloane Guy, V. Cécile, Bruno Moulin, Lhermitte Yann, T. Eric,

Pharmacological Effects and Toxicity Studies

Prior knowledge of the cytochrome 3A5 genotypes (CYP3A5*3), which contributes to the interindividual variation in the Tacrolimus (Tac) dose in kidney transplant recipients, helps tailoring the dose for a given patients, and may avoid unwanted under or overexposure. Tac is also extensively metabolized by the CYP3A4 in liver, a cytochrome with a great interindividual variation of expression. A recently described allelic variant of this cytochrome, the CYP3A4*22 allele, is associated with a decreased expression in the liver and lower global metabolic activity. Carriers of this polymorphism have a slower Tac metabolism, and may be at risk of Tac overexposure. The aim of this study is to evaluate the impact of the CYP3A4*22 allele on Tac residual concentrations and doses in 280 kidney transplant recipients who participated in a prospective, randomized, multicenter study, designed to compare the pharmacokinetic characteristics of Tac in patients receiving a fixed dose of the drug or a dose adapted according to the patient's genotype. The frequency of the CYP3A4*22 allele in the entire cohort was 7.7%, and the vast majority (90%) of the CYP3A4*22 carriers were non-expressors for the CYP3A5 (CYP3A5*3/*3). At day 10, only 10% of the CYP3A5*3/*3-CYP3A4*22 carriers were within Tac concentration ranges (10-15 mg/ml), compared to 60% with the CYP3A5*3/*3-CYP3A4*1/*1 genotype. The risk of Tac overexposure after 6 Tac doses was 12 fold higher in the CYP3A5*3/*3-CYP3A4*22 patients. At this time point, the median serum creatininemia was 191 mmol/l (142-274 mmol/l) in the CYP3A5*3/*3-CYP3A4*22 patients versus 146 mmol/l (117-200 mmol/l), in the CYP3A5*3/*3-CYP3A4*1/*1 patients, p=0.03. Two months after transplantation, the median Tac dose to reach target concentrations was CYP3A5*3/*3-CYP3A4*22 patients was 30% lower than in the CYP3A5*3/*3-CYP3A4*1/*1 patients: 0.08 mg/kg (0.05-0.11) versus 0.11 mg/kg (0.07-0.14), respectively, p=0.03. In conclusion, the CYP3A4*22 genotype, which is almost always found in the CYP3A5 non-expressors patients, is associated with a high risk of Tac overexposure at day 10 post transplantation, and carriers of this allele require 30% lower Tac dose to reach target concentrations.