Correlation Between N-Demethyl Imatinib Trough Concentration and Serious Adverse Reactions in Patients with Gastrointestinal Stromal Tumors: A Retrospective Cohort Study

Abstract

Background: Imatinib is the first-line treatment for gastrointestinal stromal tumors; however, the clinical prognosis and adverse reactions of patients vary owing to individualized discrepancies in plasma exposure. Methods: To determine the safe interval for steady-state plasma trough concentrations (Cmin) of imatinib and its active metabolite, N-demethyl imatinib (NDI), 328 plasma samples from 273 patients treated with imatinib were retrospectively analyzed. Imatinib Cmin and NDI Cmin were tested, and adverse reactions were recorded. The association between imatinib Cmin, NDI Cmin, and serious adverse reactions was evaluated. Results: The Cmin range of imatinib was 209.5–4950.0 ng/mL, with the mean value and SD of 1491.8 ± 731.4 ng/mL. The Cmin range of NDI was 80.0–2390.0 ng/mL with the mean value and SD of 610.8 ± 281.5 ng/mL. NDI Cmin was positively correlated with imatinib Cmin, whereas the ratio of NDI Cmin to imatinib Cmin (NDI Cmin/imatinib Cmin) was negatively correlated with imatinib Cmin. Univariate logistic regression analysis demonstrated that the treatment objective, daily dose, imatinib Cmin, NDI Cmin, and imatinib Cmin + NDI Cmin were significantly associated with serious adverse reactions. Multivariate logistic regression analysis showed that NDI Cmin was an independent risk factor for serious adverse reactions, with a threshold of 665 ng/mL. Conclusions: NDI Cmin was an independent risk factor for serious adverse reactions, with a threshold of 665 ng/mL. Monitoring NDI Cmin was beneficial for the rational application of imatinib and individualized treatment of patients with gastrointestinal stromal tumors.