Influence of CYP3A5 genotypes on tacrolimus dose requirement: age and its pharmacological interaction with ABCB1 genetics in the Chinese paediatric liver transplantation.

AIM: The purpose of the study was to evaluate the impact of single nucleotide polymorphisms (SNPs) of Cytochrome P450 (CYP) 3A5 and adenosine triphosphate-binding cassette B1 (ABCB1) genotypes on TAC pharmacokinetics in Chinese paediatric patients.

METHOD: A total of 136 Chinese paediatric liver recipients (R) and their donors (D) were divided into groups according to their CYP3A5 genotypes [expression of *1 allele: expressor (EX) or non-expressor (NEX)].

RESULT: Both recipient and donor CYP3A5*1 alleles had impacts on the TAC pharmacokinetics after liver transplantation. EX-R/EX-D recipients required a significantly higher TAC daily dose compared with NEX-R/NEX-D (0.24 ± 0.08 vs. 0.14 ± 0.06 mg/kg/day, p < 0.01). Age was also an independent factor on TAC requirement. Compared with EX-R/EX-D, non-expressor infants or recipients over 3-years old needed < 0.2 mg/kg/day. None of the ABCB1 SNPs (1236C>T, 2677G>A/T, 3435C>T) had an impact on TAC pharmacokinetics. However, EX-R/EX-D recipients bearing the ABCB1 1236-CC genotype required a much higher TAC dose than those without this genotype (0.23 vs. 0.18 mg/kg/day, p < 0.01), who required a similar TAC dose to that of NEX-R/NEX-D children. Furthermore, EX-R/EX-D with ABCB1 1236-CC recipients exhibited an markedly higher incidence of acute rejection and transplant-related infections clinically.

CONCLUSION: CYP3A5 and ABCB1-1236 genotyping, in addition to recipient age, are necessary for establishing a more accurate TAC dosage regimen in paediatric liver recipients. We should be cautious regarding the treatment of paediatric recipients with both CYP3A5-expressor and ABCB1 1236-CC genotypes with TAC, as these patients are more susceptible to acute rejection and infection.