Can therapeutic drug monitoring increase the safety of Imatinib in GIST patients?

Abstract

Imatinib at 400 mg daily is the standard treatment for patients affected with CML and GIST. The intervariability in plasma concentration is very significant. In many reports, a good therapeutic effect is attributed to an adequate concentration of Imatinib. However, few studies have been conducted to investigate the association between plasma concentration and side effects. Besides, no upper concentration limit of Imatinib plasma concentration detection has been established. The correlation of Imatinib trough concentrations (Cmin) with adverse effects (AEs) was described here. Plasma samples were obtained from patients after 3 months treatment with Imatinib (steady state, n = 122). Liquid chromatography/ tandem mass spectrometry was used to determine the concentration of Imatinib and its metabolite NDI. The incidence of myelosuppression was increased significantly with the increased Imatinib trough plasma concentration. The plasma level of Imatinib and NDI in patients who developed myelosuppression are 1698.3 ± 598.6 ng/mL and 242.1 ng/mL, respectively, which were significantly higher than those in patients who did not (1327.2 ± 623.4 ng/mL, P = 1.75 × 10‐4; 206.3 ng/mL, P = 0.006). Estimated exposure thresholds of Imatinib and NDI were 1451.6 ng/mL with ROCAUC (95%CI) of 0.693 (0.597–0.789) and 207.1 ng/mL with ROCAUC (95%CI) of 0.646 (0.546–0.745), respectively. Multivariate regression confirmed the correlation of Imatinib Cmin with myelosuppression. Other side effects such as fluid retention and rash were not found to be correlated with Imatinib concentrations. These results suggest that trough concentration of Imatinib should be taken into consideration to increase the safety of Imatinib therapy in GIST patients.

Comparison of Dasatinib- and Imatinib-Related Cardiotoxic Adverse Events in Japanese Patients With Chronic Myeloid Leukemia and Gastrointestinal Stromal Tumor

“… 31 We believe that the differences in AEs between the 2 drugs would not be affected, even if the 2 types of diseases treated with imatinib were included in the analysis. Third, some AEs, such as pleural effusion and myelosuppression, 32 , 33 are known to be dependent on the dose of TKIs. In the present study, the mean doses of dasatinib and imatinib were 98.8±26.8 and 356.8±87.3 mg daily, respectively, which correspond to the standard doses for these drugs.…”

Individualized Management of Blood Concentration in Patients with Gastrointestinal Stromal Tumors

“…50 Another study shows that patients with higher blood concentrations are more likely to develop thrombocytopenia, 51 and that patients with blood concentrations of higher than 1451.6 ng/mL of IM were more likely to develop myelosuppression. 52 A study found that higher protein levels in the body can significantly reduce the concentrations of free IM and N-desmethyl-imatinib, thus affecting their pharmacological effects. This study also found that the adverse effects of IM were related to the blood concentration of N-desmethyl-imatinib.…”

Factors Influencing the Steady-State Plasma Concentration of Imatinib Mesylate in Patients With Gastrointestinal Stromal Tumors and Chronic Myeloid Leukemia

“…In this section, we focus on the factors affecting the plasma concentrations of IM in patients with GISTs or CML, respectively. Because the potency of NDI is similar to that of IM in vitro, the concentration of NDI is frequently determined along with IM concentrations in TDM studies (Zhuang et al, 2018).…”

“…Interpatient differences in therapeutic response may occur partly because of pharmacokinetic (PK) variability, which has been estimated to be ∼60 and 71% in IM steady-state trough concentrations in patients with GISTs or CML, respectively (Gandia et al, 2013;Zhuang et al, 2018). PK variability, which is mainly caused by physiological, pathological, genetic, demographic, and environmental factors, manifests as a broad range of plasma trough levels (C min ) in patients receiving the same dosage, usually 400 mg/d of IM (Widmer et al, 2014).…”