Frequency of CYP3A5 Genetic Polymorphisms and Tacrolimus Pharmacokinetics in Pediatric Liver Transplantation

Abstract

The evidence available in the pediatric population is limited for making clinical decisions regarding the optimization of tacrolimus (TAC) in pharmacotherapy. The objective of this study was to estimate the frequency of CYP3A5 genetic polymorphisms and their relationship with tacrolimus requirements in the pediatric population. This was a longitudinal cohort study with a two-year follow-up of 77 patients under 18 years old who underwent a liver transplant during the period 2009–2012 at the J.P. Garrahan Pediatric Hospital. Tacrolimus levels from day five up to two years after the transplant were obtained from hospital records of routine therapeutic drug monitoring. The genotyping of CYP3A5 (CYP3A5*1/*3 or *3/*3) was performed in liver biopsies from both the donor and the recipient. The frequency of CYP3A5*1 expression for recipients was 37.1% and 32.2% for donors. Patients who received an expresser organ showed lower Co/dose, especially following 90 days after the surgery. The role of each polymorphism is different according to the number of days after the transplant, and it must be taken into account to optimize the benefits of TAC therapy during the post-transplant induction and maintenance phases.

Population pharmacokinetic models of tacrolimus in paediatric solid organ transplant recipients: A systematic review

“…[46][47][48] The role of each polymorphism is different according to the number of days after the transplant. 49 In the short term, the donor liver genotype and the recipient intestine genotype exhibit almost equal contributions. In contrast, the donor genotype had a greater impact than the recipient genotype after 6 months or in long-term use.…”

“…13,52 Also, both donor and recipient CYP3A5 genotypes should be taken into account for personalized tacrolimus treatment in transplant recipients. 49,50 To date, 3 studies investigated the efficacy of genotype-based tacrolimus therapy in paediatric SOT recipients. [53][54][55] Genotype-based tacrolimus dosing tends to help transplant recipients achieve the target tacrolimus trough concentration faster after the initial dose.…”

“…Given that both intestinal and hepatic CYP3A5 enzymes play roles in the metabolism of tacrolimus, the combined contribution of CYP3A5 expression in the liver allograft and native intestine is likely to influence the PK of tacrolimus, particularly in liver transplant recipients 46–48 . The role of each polymorphism is different according to the number of days after the transplant 49 . In the short term, the donor liver genotype and the recipient intestine genotype exhibit almost equal contributions.…”

Therapeutic drug monitoring in developing nations: assessing the current state of affairs in South America

“…Brazil, the most populous Country of South America, accounts for more than half of the publications, followed by Argentina, Colombia, and Chile ( Table 1). TDM of immunosuppressants was subject of relevant studies, including a prospective randomized trial on tacrolimus therapy in kidney transplant [4], from the group from the "Hospital do Rim", a world reference center in kidney transplants located in São Paulo, Brazil, and a two years follow up study from the Argentinean "J.P. Garrahan Hospital" on pharmacogenetic and tacrolimus in pediatric liver patients [5]. Pharmacogenetic was also explored in several Brazilian studies.…”

Precision Medicine: Applied Concepts of Pharmacogenomics in Patients with Various Diseases and Polypharmacy

“…They conclude that the role of each polymorphism is different according to the number of days after the transplant. They also suggest that such polymorphism be considered to optimize the benefits of tacrolimus therapy during the post-transplant induction and maintenance phases [ 12 ]. Finally, in their study, Salvador-Martin et al aimed to identify PGx markers that could predict early response to anti-tumor necrosis factor (TNF) drugs in pediatric patients with inflammatory bowel disease.…”