CYP3A4/5 genotypes and age codetermine tacrolimus concentration and dosage in pediatric heart transplant recipients

Tacrolimus (TAC) is the cornerstone of immunosuppressive therapy for pediatric heart transplantation (HTx) recipients. However, little information is known on the interaction of developmental and genetic variants on TAC disposition in this population, which makes TAC dose optimization more difficult. The aim of study was to investigate the relationship between genotypes and age on TAC concentrations and dosage during the early post-operation period in pediatric HTx recipients. Sixty-six pediatric HTx recipients were enrolled and divided into three groups according to the age (<6, ≥6-≤12, 12-18 years old). CYP3A4/5, POR and ABCB1 polymorphisms were genotyped. The associations between genotypes and age on TAC dose-adjusted trough concentrations (C0/D), dose requirement as well as acute kidney injury (AKI) were evaluated. CYP3A5*3 and CYP3A4*1G were significantly correlated with TAC C0/D and dose requirement in the pediatric recipients ≥ 6 years. The C0/D in children aged ≥ 6-≤12 years and 12-18 years is 2.8 and 4.2 fold of these < 6 years old, respectively. TAC dose requirements in children aged < 6 years were 2.4 times and 3.5 times of these aged ≥ 6-≤12 years and 12-18 years, respectively. Among the same CYP3A5*3 or CYP3A4*1G genotypes, age was positively increased with TAC C0/D and negatively correlated with targeted dose. No genetic variants were found to be associated with AKI during the early post-operation period. CYP3A4/5 genotypes and age should be taken into consideration to TAC dosage in pediatric HTx recipients.