Population pharmacokinetics of lenalidomide in Chinese patients with influence of genetic polymorphisms of ABCB1

Abstract

Abstract Objective Affected by differences in the pharmacokinetics (PK) of lenalidomide, the toxicity of lenalidomide varies among different patients, with severe toxicity leading to dose reduction or discontinuation. The differences in the PK of lenalidomide may be related to factors such as patients’ physiological characteristics, pathological characteristics and gene polymorphisms et al., which may also affect its toxicity. The aim of this study is to establish a population pharmacokinetic (PPK) model of lenalidomide and explore factors associated with the adverse events (AEs) of lenalidomide from a PK perspective. Methods Blood samples were collected by opportunistic blood collection. Drug concentrations were determined by using HPLC/MS and genotype was tested by the first-generation DNA sequencing technology. NONMEM software and SPSS 26.0 software were used respectively to establish PPK model of lenalidomide and explore the correlation between PK parameters and the incidence of severe AEs of lenalidomide. Results A one-compartment model with first-order absorption and elimination agreed well with the observed data. The significant covariate affecting lenalidomide apparent volume of distribution (V/F) were the gene polymorphism of ABCB1 3435 C＞T and diet. The V/F value in patients suffering from severe AEs was significantly higher than that in others ( median = 67.04 L vs 37.17 L, P = 0.033). According to the covariates screened, the incidence of severe AEs was higher in patients with genotype CT or TT at ABCB1 3435 C > T locus than that in patients with genotype CC (P = 0.039). Additionally, V/F value was the highest in patients carrying genotype TT with postprandial medication, in whom the incidence of severe AEs was higher than others (P = 0.037). Conclusion The covariates screened were the genotype of ABCB1 3435 C > T locus and diet, which may be related to the incidence of severe AEs. Patients with gene mutations of CT or TT at ABCB1 3435 C > T locus may be more susceptible to severe AEs, and monitoring of adverse reactions should be particularly strengthened in patients who carried genotype TT with postprandial medication.