Association of Imatinib Plasma Concentration and Single-nucleotide Polymorphisms with Adverse Drug Reactions in Patients with Gastrointestinal Stromal Tumors

Abstract

Gastrointestinal stromal tumors (GIST) are the most prevalent mesenchymal tumors of the digestive tract. To investigate the association of imatinib mesylate plasma concentration with adverse drug reactions (ADRs) and influences of genetic polymorphisms on ADRs in GIST patients taking imatinib, a cohort of GIST patients consecutively treated with imatinib were included in the observational study. Clinical, pathologic and genotype information was recorded at enrollment and blood samples were collected at time as design. The plasma concentration of the imatinib was detected by LC-MS/MS. A questionnaire was used to evaluate the ADRs at each visit. SNPs in 13 genes were analyzed for a possible association with ADRs. The mean plasma trough concentration of 129 patients taking imatinib was 1.45 AE 0.79 mg/ml, average peak concentration was 2.63 AE 1.07 mg/ml. The imatinib concentration in patients treated with 600 mg/day was significantly higher than other dosage groups (P < 0.05). The ADRs were mostly mild. Edema, vomiting, and fatigue were significantly correlated with imatinib concentration (P < 0.05). Mutations of IL13 rs1800925 and CXCL14 rs7716492 were related with the incidence of leukopenia and rash in our research, separately (P < 0.05). We confirmed that with the increase of imatinib concentration, the incidence of edema, vomiting, and fatigue rises as well. Mutations of IL13 rs1800925 and CXCL14 rs7716492 may be the promising biomarkers to predict the ADRs of imatinib. The results of the study are of guiding significance for the use of imatinib in patients with GIST.

Correlations between imatinib plasma trough concentration and adverse reactions in Chinese patients with gastrointestinal stromal tumors

“…These results suggest that leukopenia and neutropenia were not dose‐dependent and were likely to be concentration‐independent as well, because dosage is the most important factor affecting imatinib plasma concentrations, and mean imatinib exposure increases proportionally with increasing dosage ranging from 25 to 1000 mg . Similar results were reported in another recent study of patients with GIST by Zhang et al, who demonstrated that leukopenia and imatinib plasma concentration were not significantly correlated, including both trough and peak concentrations . Therefore, the imatinib plasma concentration might not be a risk factor for leukopenia or neutropenia.…”

Renal Clearable Theranostic Nanoplatforms for Gastrointestinal Stromal Tumors

“…Importantly, IM continuation is crucial for long‐term survival of advanced GIST patients since IM typically suppresses GIST growth but does not eradicate the tumors. IM can occasionally cause serious adverse effects including myelosuppression, tumor bleeding, gastrointestinal perforation, interstitial pneumonia, and severe skin symptoms …”

Somatic pharmacogenomics of gastrointestinal stromal tumor

“…Therefore, it is conceivable that polymorphisms or gene expression regulation through methylation/miRNA mechanisms could represent key players in affecting the final clinical outcome. By virtue of this consideration, possible pharmacogenetic [57][58][59][60][61][62] and epigenetic [63][64][65][66] mechanisms of imatinib and sunitinib resistance have been broadly investigated in GISTs [67][68][69][70][71] . Despite the extensive research, data are controversial and to date none of them supports the use of pharmacogenetic or pharmacoepigenetic tests to optimize treatment outcome in GIST patients.…”