THERAPEUTIC INDIVIDUALIZATION OF TACROLIMUS AFTER TRANSPLANTATION OF LIVER: THE EFFECT OF VERTICAL GASTRECTOMY AND BIOPSY TECHNOLOGY LIQUIDS

• Grant number: 23/04406-3
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2024
• End date: January 31, 2026
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Leonardo Régis Leira Pereira
• Grantee: Leonardo Régis Leira Pereira
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Ajith Kumar Sankarankutty ; Cristiane Masetto de Gaitani ; Fabiana Rossi Varallo ; Fernanda Fernandes Souza ; José Sebastião dos Santos ; Lúcia Helena Faccioli ; Natália Valadares de Moraes ; Wilson Salgado Junior

Abstract

Solid organ transplants can save the lives of many patients with irreversible organ disease or injury.Immunosuppressive therapy with the calcineurin inhibitor tacrolimus is used to prevent and treat organ rejection. Due to the risk of organ rejection, infection, and toxicity, precision dosing strategies aim to reduce the variability in the pharmacokinetics (PK) of tacrolimus. Despite the important role of pharmacogenomics, no genetic variants define the wide expression variations for certain key enzymes, such as CYP3A4, and large expression variability can occur within each genotype, such as for CYP3A5.Plasma-derived extracellular (EV) vesicles have gained ground as new phenotypic biomarkers, alsoknown as liquid biopsy technology. EVs are released into the blood with a representative cargo of theirtissue of origin. Therefore, assessing the variability in hepatic and intestinal CYP3A4/5 expression in EVs is a promising alternative to inform precision medicine. A prospective, longitudinal crossover clinical study will be performed to evaluate tacrolimus PK on days 1-3, weeks 4-5 and 8-9 after liver transplantation. Since inflammation decreases CYP3A4 expression, we will investigate whether post-surgical inflammation affects tacrolimus PK. Another prospective crossover study will be conducted to evaluate the effect of sleeve gastrectomy on tacrolimus kinetic disposition since obesity is a risk factor for non-alcoholic steatohepatitis and non-alcoholic fatty liver disease. Levels of pro-inflammatory cytokines, genotyping data, expression data in EVs, and other demographic and clinical variables, will betested as covariates using population pharmacokinetic (PopPK) and physiological (PBPK) modeling. This will create a digital twin for each patient to develop an integrated package of highly predictive models and dosing optimization strategies for tacrolimus. (AU)