Donor CYP3A5 genotype influences tacrolimus disposition on the first day after paediatric liver transplantation

Abstract

Aim: The aim of the present study was to investigate the influence of the cytochrome P450 (CYP) 3A4/5 genotype in paediatric liver transplant recipients and donors, and the contribution of age and gender to tacrolimus disposition on the first day after transplantation.

Methods: The contribution of the CYP3A4/5 genotype in paediatric liver transplant recipients and donors to the tacrolimus blood trough concentrations (C₀ ) and the tacrolimus concentration/weight-adjusted dose ratio on day 1 was evaluated in 67 liver-transplanted children: 33 boys and 34 girls, mean age 4.5 years.

Results: Donor CYP3A5 genotype appears to be significantly associated with tacrolimus disposition on the first day after liver transplantation (P < 0.0002). Other physiological factors, such as recipient age and donor gender may also play a role and lead to significant differences in tacrolimus C₀ and tacrolimus concentration/weight-adjusted dose ratio on day 1. However, according to the general linear model, only recipient age appears to be independently associated with tacrolimus disposition on the first day after liver transplantation (P < 0.03). Indeed, there was a faster tacrolimus metabolism in children under 6 years of age (P < 0.02).

Conclusions: Donor CYP3A5 genotype, recipient age and, to a lesser extent, donor gender appear to be associated with tacrolimus disposition on day 1 after transplant. This suggests that increasing the starting tacrolimus doses in paediatric patients under 6 years of age who receive a graft from a male extensive metabolizer may enhance the possibility of their tacrolimus levels reaching the therapeutic range sooner.

Keywords: CYP3A genotyping; children; immunosuppression; liver transplantation; tacrolimus; therapeutic drug monitoring.

Figure 1

(A) Tacrolimus trough concentration (C₀) on the first day after liver transplantation in the whole paediatric population. The grey zone denotes the target therapeutic range in the first days after liver paediatric transplantation. (B) Tacrolimus concentration/weight‐adjusted dose ratio on the first day after liver transplantation in the whole paediatric population. The horizontal line in the middle indicates the median; the top and the bottom lines mark the 75th and 25th percentiles, respectively

Figure 2

Tacrolimus concentration/weight‐adjusted dose ratio on the first day after liver transplantation in paediatric patients who were younger and older than 6 years old. The horizontal line in the middle indicates the median; the top and the bottom lines mark the 75th and 25th percentiles, respectively. A P value of less than 0.05 was taken as statistically significant

Figure 3

Tacrolimus trough concentration (C₀) on the first day after liver transplantation in paediatric patients according to the CYP3A4/5 combined‐genotype approach on whole‐body metabolism. The grey zone denotes the therapeutic range in the first days after liver paediatric transplantation. The horizontal line in the middle indicates the median; the top and the bottom lines mark the 75th and 25th percentiles, respectively. RM, rapid metabolizer; EM, extensive metabolizer; IM, intermediate metabolizer. A P value of less than 0.05 was taken as statistically significant

Figure 4

(A) Tacrolimus trough concentration (C₀) on the first day after liver transplantation in paediatric patients according to liver CYP3A5 genotype. The grey zone denotes the therapeutic range in the first days after liver paediatric transplantation. (B) Tacrolimus concentration/weight‐adjusted dose ratio on the first day after liver transplantation in paediatric patients according to liver CYP3A5 genotype. The horizontal line in the middle indicates the median; the top and the bottom lines mark the 75th and 25th percentiles, respectively. A P value of less than 0.05 was taken as statistically significant