Imatinib Pharmacokinetics in a Large Observational Cohort of Gastrointestinal Stromal Tumour Patients

Background: Low trough imatinib concentration (C_min) values have been associated with poor clinical outcomes in gastrointestinal stromal tumour (GIST) patients. This study describes the pharmacokinetics of imatinib in a large cohort of GIST patients in routine clinical care. Methods: An observational study was performed in imatinib-treated GIST patients. Patient and tumour characteristics were derived from the Dutch GIST Registry and medical records. Imatinib concentrations were measured by liquid chromatography with tandem mass spectrometry. The analyses included the occurrence of a low imatinib C_min (<1000 µg/L), the change in the C_min over time and the correlation between exposure and response. Results: In total, 421 plasma samples were available from 108 GIST patients. Most patients (79.6 %) received an imatinib dose of 400 mg. The inter- and intrapatient variabilities in C_min were 54 and 23 %, respectively. In the first steady-state sample, 44.4 % of patients presented with C_min values <1000 µg/L; 32.4 % of patients had values <1000 µg/L in >75 % of their samples. Only 33.3 % of patients had C_min values ≥1000 µg/L in all measured samples. No decrease in C_min over time was found (P > 0.05). Fifty-seven (91.9 %) of 62 palliative-treated patients had a tumour response (median C_min 1271 µg/L). Five palliative patients (8.1 %) did not respond (median C_min 920 µg/L). Given the limited number of non-responders in this cohort, no statistically significant association with clinical benefit could be demonstrated. Conclusion: In routine clinical care, one third of GIST patients are systematically underexposed with a fixed dose of imatinib. Prospective clinical studies are needed to investigate the value of C_min-guided imatinib dosing in GIST patients.