Polymorphisms in CYP3A5, CYP3A4, and ABCB1 Genes: Implications for Calcineurin Inhibitors Therapy in Hematopoietic Cell Transplantation Recipients-A Systematic Review

Luiz Carlos da Costa-Junior^1,2Daniely Regina Freitas-Alves³Amanda Melo Leite Leão^4,5Hayra de Andrade Vieira Monterio⁶Rita de Cássia Barbosa da Silva Tavares²Maria Claudia Rodrigues Moreira^2,7Marília Berlofa Visacri⁸Teresa de Souza Fernandez^4*Paulo Caleb J L Santos^1,9*

• ¹Postgraduate Program in Medical Sciences, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil
• ²Bone Marrow Transplant Center, Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ, Brazil
• ³Escola Nacional de Saúde Pública Sérgio Arouca, Fundação Oswaldo Cruz (ENSP-FIOCRUZ), Rio de Janeiro, RJ, Brazil
• ⁴Cytogenetic Laboratory, Cell and Gene Therapy Program, Instituto Nacional do Câncer (INCA), Rio de Janeiro, RJ, Brazil
• ⁵Escola de Ciências da Saúde, Universidade do Grande Rio (Unigranrio), Duque de Caxias, RJ, Brazil
• ⁶Clinical Research Division, Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ, Brazil
• ⁷Bone Marrow Transplant Program, Hospital Universitário Clementino Fraga Filho (HUCFF), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
• ⁸Departament of Pharmacy, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo (FCF-USP), São Paulo, SP, Brazil
• ⁹Paulista School of Medicine, Federal University of São Paulo, São Paulo, Brazil

This systematic review assessed the impact of CYP3A5, CYP3A4, and ABCB1 polymorphisms on the pharmacokinetics and clinical outcomes of calcineurin inhibitors in hematopoietic cell transplantation (HCT) recipients. Following PRISMA 2020 guidelines, the protocol was registered in PROSPERO (CRD42024517094). A comprehensive search in PubMed, BVS, Scopus, Web of Science, Embase, and Cochrane databases (2013)(2014)(2015)(2016)(2017)(2018)(2019)(2020)(2021)(2022)(2023)(2024) identified observational studies focusing on tacrolimus or cyclosporine and the specified polymorphisms. Studies on non-human subjects, solid organ transplants, pharmacokinetic models, and drug interactions were excluded. Narrative synthesis was employed due to heterogeneity, and study quality was evaluated using the Newcastle-Ottawa Scale (NOS) and STREGA guidelines. Of 301 records, 11 studies met inclusion criteria, predominantly retrospective and involving adult populations, with sample sizes ranging from 20 to 420 HCT recipients from the USA, Japan, and France. Outcomes included drug levels, median concentration/dose (C/D) ratio, therapeutic index, and clinical endpoints such as graft-versus-host disease (GVHD) and acute kidney injury (AKI). CYP3A5*3 (rs776746) significantly influenced tacrolimus levels, C/D ratio, and clinical outcomes, highlighting its potential as a pharmacogenetic biomarker. CYP3A4 and ABCB1 polymorphisms demonstrated limited effects on tacrolimus pharmacokinetics and no significant clinical impact. Methodological quality was high, with 55% of studies achieving the maximum NOS score, although gaps in error rates and population modeling were noted. Limitations include variability in outcomes precluding meta-analysis, a small number of studies, particularly on cyclosporine, and insufficient data on CYP3A4 and ABCB1. Further research is necessary to validate findings.