Plasma concentrations of venetoclax and Pharmacogenetics correlated with drug efficacy in treatment naive leukemia patients: a retrospective study

Abstract

Introduction: Venetoclax (VEN) was the only Bcl-2 inhibitor approved by FDA and showed desired efficacy. However, VEN showed large differences in clinical efficacy, which may due to pharmacokinetic variability. Objectives:The purpose of the study was to explore the relationships between the plasma concentration and efficacy of VEN, and identify potential influencing factors. Methods: A retrospective cohort study was conducted in the First Affiliated Hospital of Nanchang University from March 2022 to March 2024. LC-MS/MS was used to monitor the concentration of VEN. Pharmacogenetics was determined by DNA sequence. Results: A total of 76 trough (C_0h) and 91 6h post-dose plasma concentration (C_6h) blood concentrations of VEN were collected in 54 patients. C_6h/D concentration of VEN was significantly correlated with treatment efficacy (P = 0.006) in Leukemia patients with good or intermediate prognosis. A ROC curve was then established and the cut-off value was calculated as 0.2868 µg/ml.kg.mg-1(AUC = 0.7097, P = 0.1081). Furthermore, the research uncovered correlations among the co-administration of triazoles, CYP3A5 rs776746 and ABCB1 genotypes with VEN plasma concentrations. Through LASSO-logistic regression and nomagram analysis, ELN prognostic stratification and neutrophil percentages were determined as the critical elements that may predict drug response. Conclusions: Our results confirmed that ELN stratification was applicable in predicting drug response in treatment native unfit AML patients. C_6h/D level may correlate with drug response especially in good and moderate stratification patients. Patients co-administered with triazoles or carried with AA/AG CYP3A5 rs776746 should be paid more attention in order to attain sustainable efficacy with limited toxicity.