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 (C_min) 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 ROC_AUC (95%CI) of 0.693 (0.597–0.789) and 207.1 ng/mL with ROC_AUC (95%CI) of 0.646 (0.546–0.745), respectively. Multivariate regression confirmed the correlation of Imatinib C_min 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.

Since Imatinib is usually administered for a prolonged period, rational management of its side effects is of great importance. Few studies have been conducted to investigate the association between plasma concentration and side effects. In this study, Imatinib-induced myelosuppression was found to be correlated significantly with Imatinib concentration, and the estimated exposure threshold for myelosuppression was 1451.6 ng/mL with ROCAUC (95% CI) of 0.693 (0.597–0.789).

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