Early impact of donor CYP3A5 genotype and Graft-to-Recipient Weight Ratio on tacrolimus pharmacokinetics in pediatric liver transplant patients

Michele Pinon,Antonio D’Avolio,Silvia Catalano,Dominic Dell’Olio,Antonio Pizzol,Miriam Antonucci,Roberto Canaparo,Pier Luigi Calvo,Francesco Tandoi,Amedeo De Nicolò,Loredana Serpe,Renato Romagnoli

doi:10.1038/s41598-020-79574-7

Abstract

Tacrolimus (TAC) pharmacokinetics is influenced by the donor CYP3A5 genotype and the age of pediatric liver recipients. However, an optimization of a genotype-based algorithm for determining TAC starting is needed to earlier achieve stable target levels. As the graft itself is responsible for its metabolism, the Graft-to-Recipient Weight Ratio (GRWR) might play a role in TAC dose requirements. A single-center study was carried out in a cohort of 49 pediatric recipients to analyse the impact of patient and graft characteristics on TAC pharmacokinetics during the first 15 post-transplant days. Children < 2 years received grafts with a significantly higher GRWR (4.2%) than children between 2–8 (2.6%) and over 8 (2.7%). TAC concentration/weight-adjusted dose ratio was significantly lower in recipients from CYP3A5*1/*3 donors or with extra-large (GRWR > 5%) or large (GRWR 3–5%) grafts. The donor CYP3A5 genotype and GRWR were the only significant predictors of the TAC weight adjusted doses. Patients with a GRWR > 4% had a higher risk of acute rejection, observed in 20/49 (41%) patients. In conclusion, TAC starting dose could be guided according to the donor CYP3A5 genotype and GRWR, allowing for a quicker achievement of target concentrations and eventually reducing the risk of rejection.

Highlights

Tacrolimus (TAC) pharmacokinetics is influenced by the donor CYP3A5 genotype and the age of pediatric liver recipients
The TAC pharmacokinetic analysis we performed in the first two post-transplant weeks confirmed some results from our previous s tudy[12], where the donor CYP3A5 genotype and the recipient age explained part of the inter-individual variability in TAC concentrations
We confirmed that patients receiving a liver from donors heterozygous for the CYP3A5*3 allele have higher dose requirements compared to those who are homozygous for the CYP3A5*3 allele, as previously reported[8,9,10,11], suggesting that the hepatic metabolism is determinant on TAC blood concentrations immediately after the transplant, regardless of the impaired hepatic synthetic function, which characterizes the early post-transplant period

Summary

Introduction

Tacrolimus (TAC) pharmacokinetics is influenced by the donor CYP3A5 genotype and the age of pediatric liver recipients. A single-center study was carried out in a cohort of 49 pediatric recipients to analyse the impact of patient and graft characteristics on TAC pharmacokinetics during the first 15 post-transplant days. TAC concentration/weight-adjusted dose ratio was significantly lower in recipients from CYP3A5*1/*3 donors or with extra-large (GRWR > 5%) or large (GRWR 3–5%) grafts. The donor CYP3A5 genotype and GRWR were the only significant predictors of the TAC weight adjusted doses. TAC starting dose could be guided according to the donor CYP3A5 genotype and GRWR, allowing for a quicker achievement of target concentrations and eventually reducing the risk of rejection. The introduction of the calcineurin inhibitor drug tacrolimus (TAC) has improved patient survival in pediatric liver transplant patients. Better strategies for TDM are required to establish the optimal TAC dosage, especially in the early post-transplant period[4]

Methods

Results

Conclusion