Biotransformation enzymes and transporters: A pharmacogenetic study in renal transplant recipients treated with tacrolimus, everolimus and mycophenolate sodium

• Grant number: 17/19098-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2018
• End date: October 31, 2019
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Rosario Dominguez Crespo Hirata
• Grantee: Fabiana Dalla Vecchia Genvigir
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 18/16212-0 - Comparative pharmacogenetic study in Brazilian and Spanish kidney transplant recipients treated with tacrolimus and mycophenolate sodium, BE.EP.PD

Abstract

Understanding the genetic factors involved in variations in responses to immunosuppressants can improve efficacy and limit toxicity in transplant therapy. This pharmacogenetic study aims to investigate associations between genetic polymorphisms that affect the pharmacokinetics of tacrolimus (TAC), everolimus (EVR), and mycophenolate sodium (MPS) and the clinical outcomes in kidney transplant recipients. For this purpose, renal transplant recipients were selected from two clinical studies, TIMO (n = 288) and TIMO-DCE (129), the latter was a study of deceased donors with expanded selection criteria. Patients were treated with basiliximab or thymoglobulin in addition to either EVR + TAC or MPS + TAC. Pharmacological monitoring and clinical evaluations of efficacy (i.e., rejection episodes and renal function analysis) and safety (i.e., monitoring of adverse events) were carried out for 12 months after the surgical procedure. Polymorphisms in genes that encode biotransformation enzymes (CYP2C8*3, CYP2J2*7, CYP3A4*1B, CYP3A4*1G, CYP3A4*22, CYP3A5*3C, and CYP3A5*1D), membrane transporters of efflux (ABCB1 c.1236C>T, c.3435C>T, and c.2677G>T/A; ABCC2 c.-24C>T, c.1249G>A, and c.3972C>T; ABCG2 c.421C>A), and membrane transporters of influx (SLCO1B1 c.388A>G, and c.521T>C; SLCO2B1 c.-71T>C) will be identified by real-time PCR. The findings of this study will inform the effects of genetic variants on variable responses to the immunosuppressive therapies that are used in kidney transplantation. They will also provide potentially useful data related to personalized therapy to improve overall patient and graft survival.