61 research outputs found
Towards a pharmacologically guided individualization of imatinib and sunitnib therapy
The approval of imatinib mesylate (Gleeve) in 2001 has added a new class of drugs to
the systemic treatment of cancer: that of the tyrosine kinase inhibitors (TKIs). Imatinib
inhibits autophosphorylation of specific proteins involved in oncogenesis such as the
BCR-ABL fusion protein (expressed in Philadelphia chromosome positive chronic myeloid
leukemia), c-KIT (expressed in gastrointestinal stromal tumors; GIST) and the plateletderived
growth factor receptor (PDGFR; i.e. expressed in GIST and several sarcomas).
After a decade of therapeutic use, imatinib has proven to be a highly effective targeted
agent with a median overall survival in advanced GIST patients close to 5 years
Prospective Analysis in GIST Patients on the Role of Alpha-1 Acid Glycoprotein in Imatinib Exposure
Background: For imatinib, a relationship between systemic exposure and clinical outcome has been suggested. Importantly, imatinib concentrations are not stable and decrease over time, for which several mechanisms have been suggested. In this study, we investigated if a decrease in alpha-1 acid glycoprotein (AGP) is the main cause of the lowering in imatinib exposure over time. Methods: We prospectively measured imatinib trough concentration (Cmin) values in 28 patients with gastrointestinal stromal tumours, at 1, 3 and 12 months after the start of imatinib treatment. At the same time points, AGP levels were measured. Results: Overall, imatinib Cmin and AGP levels were correlated (r2 = 0.656; P < 0.001). However, AGP levels did not fluctuate significantly over time, nor did the change in AGP levels correlate with the change in the imatinib Cmin. Conclusion: We showed that systemic AGP levels are not likely to be a key player in the decrease in systemic imatinib exposure over time. As long as intra-individual changes in imatinib exposure remain unexplained, researchers should standardize the sampling times for imatinib in order to be able to assess the clinical applicability of therapeutic drug monitoring
Tumor Volume as an Alternative Response Measurement for Imatinib Treated GIST Patients
Background: Assessment of tumor size changes is crucial in clinical trials and patient care. We compared imatinib-induced volume changes of liver metastases (LM) from gastro-intestinal stromal tumors (GIST) to RECIST and Choi criteria and their association with overall survival (OS). Methods: LM from 84 GIST p
Myelosuppression by sunitinib is flt-3 genotype dependent
Personalised Therapeutic
Influence of probenecid on the pharmacokinetics and pharmacodynamics of sorafenib
Prior studies have demonstrated an organic anion transporter 6 (OAT6)-mediated accumulation of sorafenib in keratinocytes. The OAT6 inhibitor probenecid decreases sorafenib uptake in skin and might, therefore, decrease sorafenib-induced cutaneous adverse events. Here, the influence of probenecid on sorafenib pharmacokinetics and toxicity was investigated. Pharmacokinetic sampling was performed in 16 patients on steady-state sorafenib treatment at days 1 and 15 of the study. Patients received sorafenib (200–800 mg daily) in combination with probenecid (500 mg two times daily (b.i.d.)) on days 2–15. This study was designed to determine bioequivalence with geometric mean Area under the curve from zero to twelve hours (AUC0–12 h) as primary endpoint. During concomitant probenecid, s
Integrating Clinical Pharmacology Concepts in Individualized Therapy With Tyrosine Kinase Inhibitors
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