Comparison of Tacrolimus Starting Doses Based on CYP3A5 Phenotype or Genotype in Kidney Transplant Recipients

被引:7
作者
Largeau, Berenger [1 ]
Barin-Le Guellec, Chantal [2 ]
Longuet, Helene [3 ]
Lesne, Philippe [1 ]
Bouvarel, Antoine [1 ]
Preteseille, Laura [1 ]
Marquet, Pierre [4 ]
Halimi, Jean-Michel [5 ]
Buchler, Matthias [5 ]
Gatault, Philippe [5 ]
Noble, Johan [3 ]
机构
[1] CHRU Tours, Lab Biochim & Biol Mol, F-37000 Tours, France
[2] Univ Tours, Univ Limoges, INSERM,UMR 1248,CHRU Tours,Lab Biochim & Biol Mol, Individual Profiling & Prevent Risks Immunosuppre, Tours, France
[3] CHRU Tours, Serv Nephrol Hypertens Arterielle Dialyses & Tran, FHU SUPORT, Tours, France
[4] Univ Limoges, INSERM, IPPRITT, UMR 1248,CHU Limoges,Serv Pharmacol & Toxicol,FHU, Limoges, France
[5] Univ Tours, T2I, EA4245,FHU SUPORT, CHRU Tours,Serv Nephrol Hypertens Arterielle Dial, Tours, France
关键词
kidney transplantation; tacrolimus; pharmacogenetics; CALCINEURIN INHIBITORS; GENETIC-VARIANTS; CLEARANCE; RISK; POLYMORPHISM; VARIABILITY; REJECTION; EXPOSURE; EQUATION; EFFICACY;
D O I
10.1177/1526924819873905
中图分类号
R61 [外科手术学];
学科分类号
摘要
Background: Selection of expected phenotypes (ie, expressers/non-expressers) is currently used in CYP3A5*3 genotype-based tacrolimus dosing. The authors assessed whether a dosing regimen based on the 3 CYP3A5 genotypes may reduce the occurrence of inadequate exposure. Methods: Tacrolimus whole blood trough levels (C-0) were retrieved from a retrospective cohort of 100 kidney transplant recipients treated with a starting dose of 0.15 (non-expressers) or 0.30 (expressers) mg/kg/d. The authors evaluated the occurrence of overexposures (12 < C-0 < 20 ng/mL) or toxic concentrations (C-0 >= 20 ng/mL). These results were used to set up a new strategy based on the 3 distinct CYP3A5 genotypes, which relevance was evaluated in a prospective cohort of 107 patients. Results: In the retrospective cohort, non-expressers exhibited frequent overexposure (63.6%) or toxic C-0 (20.8%). Among expressers, none of the homozygous *1 carriers exhibited overexposure contrary to 25% of the heterozygotes. Based on these results, new tacrolimus starting doses were set at 0.10, 0.20, and 0.30 mg/kg/d for CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1 genotypes, respectively. Tacrolimus overexposure was reduced in the CYP3A5*3/*3 group (63.6% vs 40%, P = .0038). None of the heterozygous patients exhibited toxic tacrolimus C-0. Clinical outcomes were not different between the 2 periods, whatever the genotype. Our results indicate that the best tacrolimus exposure was obtained for doses of 0.10, 0.20, and 0.20 mg/kg/d for CYP3A5*3/3, CYP3A5*1/*3, and CYP3A5*1/*1, respectively. Conclusions: Our results confirm that selecting tacrolimus dosing regimen according to the expected phenotype is appropriate, but that lower than currently recommended doses may be preferable.
引用
收藏
页码:300 / 308
页数:9
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