Tacrolimus Dose Requirement in Pediatric Liver Transplantation: Influence of CYP3A5 Gene Polymorphism

Abstract

Aim: Little information is available regarding the influence of CYP3A5 genetic polymorphisms on tacrolimus dose requirement in pediatric liver transplantation. Patients & methods: We performed a retrospective study among 179 pediatric liver recipients grafted between 2002 and 2009 in order to determine the influence of donor CYP3A5 genotype along with clinical variables on tacrolimus daily dose requirement during the first weeks following transplantation. Results: Mean stable tacrolimus daily dose requirement was higher among children who received a liver expressing CYP3A5 (carrying the CYPA3A5*1 allele) compared with those with a liver that did not express CYP3A5 (CYP3A5*3/*3 genotype): 0.29 ± 0.20 vs 0.18 ± 0.13 mg.kg^-1.d^-1, p = 0.005, respectively. A younger recipient age and fluconazole prescription were also significantly associated with tacrolimus daily dose requirement. Time to reach stable tacrolimus therapeutic trough concentrations was prolonged among patients with a CYP3A5-expressing graft (26 vs 21 days, p = 0.04). Conclusion: Donor CYP3A5 genotype partially explains tacrolimus dose requirement.

Original submitted 30 January 2013; Revision submitted 2 May 2013

KEYWORDS::

• CYP3A5
• pediatric liver transplantation
• pharmacogenetics
• tacrolimus

Authors‘ contribution

P Durand: conception of the study design, inclusion of patients, analysis of data and writing the paper; D Debray: conception of the study design, inclusion of patients, analysis of data and writing the paper; M Kolaci: conception of the study design, inclusion of patients, biological analysis, analysis of data and writing the paper; J Bouligand: conception of the study design, biological analysis, analysis of data and writing the paper; V Furlan: conception of the study design, inclusion of patients, biological analysis, analysis of data and writing the paper; M Fabre: conception of the study design, inclusion of patients, histological analysis of data and writing the paper; A Letierce: conception of the study design, analysis of data and writing the paper; C Piedvache: reanalysis of the study data according to reviewers suggestions; C Verstuyft: analysis of data and writing the paper; L Becquemont: conception of the study design, analysis of data, writing the paper and corresponding author.

Acknowledgements

The authors wish to acknowledge the help provided by C Piedvache for the independent and complete statistical reanalysis of the data.

Financial & competing interests disclosure

L Becquemont received consulting fees from Sanofi-Aventis, Pfizer and Servier, and lecture fees from Genzyme, GlaxoSmithKline, Bristol-Myers Squibb and Merck Sharp and Dohme. His wife works for Sanofi-Aventis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

L Becquemont received consulting fees from Sanofi-Aventis, Pfizer and Servier, and lecture fees from Genzyme, GlaxoSmithKline, Bristol-Myers Squibb and Merck Sharp and Dohme. His wife works for Sanofi-Aventis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.