Genetic Polymorphisms and Adverse Events on Unbound Imatinib and Its Active Metabolite Concentration in Patients With Gastrointestinal Stromal Tumors

Abstract

Imatinib is a first-line drug for the treatment of gastrointestinal stromal tumors (GIST). This study aims to investigate the influence of different kinds of protein concentrations and genetic polymorphisms of metabolizing enzymes and drug transporters on unbound imatinib and its active metabolite N-desmethyl-imatinib concentration, as well as the relationship between adverse drug reactions (ADRs) and drug concentration. A total of 62 Chinese patients with GIST were genotyped for five single nucleotide polymorphisms (SNPs). Total and unbound 3h and trough concentration of imatinib and N-desmethyl-imatinib in GIST patients were determined by an LC-MS/MS method combined with an equilibrium dialysis. Single-Use Red Plate with inserts was used to separate the unbound drug. When the protein concentration became higher, the unbound imatinib and N-desmethyl-imatinib plasma concentration got higher ( p < 0.05). Patients with GA genotype in rs755828176 had significantly higher unbound N-desmethyl-imatinib dose-adjusted trough plasma concentrations ( p = 0.012). Patients with CC genotype in rs3814055 had significantly higher unbound imatinib dose-adjusted trough plasma concentrations ( p = 0.040). The mean total imatinib C 3h of patients with ADRs (3.10 ± 0.96 µg/ml) was significantly higher than that of patients without ADRs ( p = 0.023). The mean total N-desmethyl-imatinib C 3h of patients (0.64 ± 0.21 µg/ml) with ADRs was significantly higher than that of patients without ADRs ( p = 0.004). The mean unbound N-desmethyl-imatinib C 3h of patients with ADRs (6.49 ± 2.53 ng/ml) was significantly higher than that of patients without ADRs ( p = 0.042). The total and unbound C 3h of imatinib and N-desmethyl-imatinib in patients with ADRs was significantly higher than that in patients without ADRs ( p < 0.05). Protein concentrations have great influence on the unbound imatinib and N-desmethyl-imatinib concentrations. The genetic polymorphisms of CYP3A4 rs755828176 and NR1I2 rs3814055 were significantly associated with unbound imatinib and N-desmethyl-imatinib dose-adjusted trough plasma levels. The total and unbound imatinib or N-desmethyl-imatinib concentration in patients with GIST was also significantly correlated with ADRs.

Pregnane X Receptor (PXR) Polymorphisms and Cancer Treatment

“…Asian patients with gastrointestinal stromal tumors (GISTs) carrying the T allele at NR1L2 rs3814055 (C > T) exhibited lower steady-state imatinib dose-adjusted plasma concentrations than patients with the wild type (CC), while in the same study patients carrying the mutant T allele at NR1L2 rs3814055 (C > T) showed significantly lower incidence rate of continuous edema, an adverse effect of imatinib [61]. These results are in agreement with the results from Yi Qian et al where patients with the TT genotype of NR1I2 rs3814055 (C > T) were described to have lower unbound imatinib dose-adjusted concentration [62].…”

The Impact of Plasma Protein Binding Characteristics and Unbound Concentration of Voriconazole on Its Adverse Drug Reactions

“…Unbound and bound VRC of all plasma samples from patients and in vitro samples were separated using rapid equilibrium dialysis (RED, Thermo Fisher Scientific, USA) (Qian et al, 2019). In brief, unbound VRC was separated from plasma in a 96-well plate with a semipermeable membrane through which only unbound drug can permeate.…”

Determination of Free Valproic Acid Concentration in 569 Clinical Samples by LC-MS/MS After Hollow Fiber Centrifugal Ultrafiltration Treatment

“…12 The total and unbound imatinib concentrations in patients with gastrointestinal stromal tumors correlated significantly with ADRs. 13,14 Brake 15 assessed the effect of malnutrition on the steady-state pharmacokinetics of total and proteinunbound rifampin in Indonesian subjects. The large interindividual variability in the free fraction of rifampin suggests that protein-unbound rather than total rifampin concentrations should preferably be used to study exposure-response relationships.…”