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

• Published in: Scientific reports Vol. 11; no. 1; pp. 443 - 13
• Main Authors: Pinon, Michele, De Nicolò, Amedeo, Pizzol, Antonio, Antonucci, Miriam, D’Avolio, Antonio, Serpe, Loredana, Dell’Olio, Dominic, Catalano, Silvia, Tandoi, Francesco, Romagnoli, Renato, Canaparo, Roberto, Calvo, Pier Luigi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/436/108; 631/154/436/1729; 631/154/436/434; 631/208/2489/1512; 692/4020/4021/288; 692/698/2741/288; Children; Genotype & phenotype; Genotypes; Graft rejection; Humanities and Social Sciences; Liver transplantation; Liver transplants; multidisciplinary; Pediatrics; Pharmacokinetics; Risk reduction; Science; Science (multidisciplinary); Tacrolimus
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-79574-7

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.