Abstract
Kinase inhibitors are small-molecule drugs designed to target oncogenic mutations in cancer treatment. Although less toxic than conventional chemotherapy drugs, they can cause severe adverse effects in some patients, resulting in dose reduction and cessation. To evaluate if therapeutic drug monitoring of kinase inhibitors and their metabolites can improve toxicity assessment in patients, we developed and evaluated the analytical performance of two parallel methods utilizing liquid chromatography (LC) and paper spray (PS) ionization coupled with a triple quadrupole mass spectrometer (MS) for the measurement of dabrafenib, its major metabolite OH-dabrafenib, and trametinib in patient plasma samples. The PS-MS method yielded a faster sample analysis time (2 min) compared to the LC separation (9 min). The two methods shared the same analytical measurement range (AMR) for dabrafenib and OH-dabrafenib (10-3500 and 10-1250 ng/mL), but the AMR differed for trametinib (LC-MS: 0.5-50 ng/mL; PS-MS: 5.0-50 ng/mL). The imprecision across their respective AMR was 1.3-6.5% (dabrafenib), 3.0-9.7% (OH-dabrafenib), and 1.3-5.1% (trametinib) for the LC-MS method and 3.8-6.7% (dabrafenib), 4.0-8.9% (OH-dabrafenib), and 3.2-9.9% (trametinib) for the PS-MS method. Using authentic patient samples, the quantification results were comparable between the two methods: dabrafenib (correlation coefficient r = 0.9977), OH-dabrafenib (r = 0.885), and trametinib (r = 0.9807). Nonetheless, the PS-MS method displayed significantly higher variations compared with the LC-MS method. Based on the LC-MS method, we were able to profile the concentrations and metabolism patterns of dabrafenib and trametinib in patients who were receiving the drugs for BRAF V600 mutation-driven malignancies.