The CYP3A5 single nucleotide polymorphism on tacrolimus dose requirements in paediatric liver transplantation

R Canaparo1, A Brunati2, D Bongioanni3, L Serpe1, E Bovio1, E Imbalzano1, F Foglietta1, PL Calvo4. 1Università degli Studi di Torino, Drug Science and Technology, 10125, Italy, 2San Giovanni Battista Hospital, Transplant Unit, 10126, Italy, 3Università degli Studi di Torino, Genetics, Biology and Biochemistry, 10126, Italy, 4Regina Margherita Children\'s Hospital, Pediatrics, 10126, Italy

Nowadays, tacrolimus (FK-506) is considered the cornerstone immunosuppressant in paediatric liver transplantation. In vitro studies demonstrated that tacrolimus inhibits calcineurin phosphatase activity, an important T-cell activation mediator, making it potent immunosuppressive agent. Tacrolimus has a large variability in both pharmacokinetics and pharmacodynamics, a narrow therapeutic index and serious toxic effects e.g. nephrotoxicity, neurotoxicity, gastrointestinal disorders, diabetes, infections and, in the long run, the onset of lymphoma. Therefore, it is essential the dosage be carefully balanced on an individual basis, as in paediatric liver transplantation its variability seems to be even more pronounced. To date, this drawback has been overcome by adjusting the daily dose on the basis of the whole-blood through concentration determined immediately before the subsequent doses. However, this strategy poses some disadvantages e.g. subtherapeutic or supratherapeutic dosing during the initial stages and not always does the target concentration guarantee a complete efficacy/absence of toxic side-effects. Consequently, it has been suggested that pharmacogenetics could overcome these drawbacks and aid drug therapy optimization. It has been shown that genetic polymorphisms (SNPs) in Cytochrome P450 enzymes, mainly CYP3A5 where the variant CYP3A5*3 gives rise to a truncated protein making them unable to metabolize the FK-506, might affect the pharmacokinetic and pharmacodynamic variability of tacrolimus, especially in paediatric liver transplantation. Therefore, our study assessed and correlated tacrolimus dose requirements with CYP3A5*3 polymorphism on genetic material obtained from the paediatric liver transplant recipients and liver donors. TaqMan® SNP genotyping assays were used to genotype CYP3A5*3 [6986A>G] in 89 paediatric liver transplant recipients and 97 liver donors. Eight paediatric liver transplant recipients were not genotyped due to lack of genetic material. Only 1% of the paediatric liver transplant recipients had a wild type CYP3A5*1/*1 genotype, while 10.1% had a heterozygous CYP3A5*1/*3 genotype and 88.8% a homozygous CYP3A5*3 /*3 genotype. In the liver donor population, 73.2% had a CYP3A5*3/*3 genotype, while 26.8% of the population was heterozygous CYP3A5*1/*3. No liver donors carrying a wild type genotype were identified. The data obtained are in agreement with international literature on Caucasian populations, where there was a predominance of the homozygous genotype for the CYP3A5*3/*3 and in line with the Hardy-Weinberg law of genetic equilibrium. Moreover, in 32 paediatric liver transplant patients a different CYP3A5 genotype was observed between recipients and liver donors with a still poorly investigated chimerism in terms of tacrolimus availability. However, tacrolimus dose requirements were significantly higher in paediatric transplant patients with one copy of the CYP3A5*1 allele compared to subjects homozygous for the CYP3A5*3 allele. These findings suggest that the pharmacogenetic analysis of CYP3A5 could help to determine the appropriate initial dosage of tacrolimus in paediatric liver transplantation.