Simultaneous quantification of dabrafenib and trametinib in human plasma using high-performance liquid chromatography-tandem mass spectrometry
Autor: | Nijenhuis, C M, Haverkate, H, Rosing, H, Schellens, J H M, Beijnen, J H, Sub Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology |
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Přispěvatelé: | Sub Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology |
Jazyk: | angličtina |
Rok vydání: | 2016 |
Předmět: |
HPLC–MS/MS
Pyridones Clinical Biochemistry Pharmaceutical Science Pyrimidinones Therapeutic drug monitoring Tandem mass spectrometry 01 natural sciences High-performance liquid chromatography Analytical Chemistry 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Limit of Detection Tandem Mass Spectrometry Liquid chromatography–mass spectrometry Trametinib Oximes Drug Discovery medicine Humans 030212 general & internal medicine Chromatography High Pressure Liquid Spectroscopy Detection limit Chromatography medicine.diagnostic_test Chemistry Dabrafenib 010401 analytical chemistry Imidazoles Reproducibility of Results 0104 chemical sciences Calibration medicine.drug |
Zdroj: | Journal of Pharmaceutical and Biomedical Analysis, 125, 270. Elsevier |
ISSN: | 0731-7085 |
Popis: | Dabrafenib (Tafinlar(®)) and trametinib (Mekinist(®)) are registered for the treatment of patients with BRAF V600 mutation positive unresectable or metastatic melanoma. To support therapeutic drug monitoring (TDM) and clinical pharmacological trials, an assay to simultaneously quantify dabrafenib and trametinib in human plasma using liquid chromatography tandem mass spectrometry was developed and validated. Human plasma samples were collected on an outpatient base and stored at nominally -20°C. Analytes and internal standards (stable isotope labeled compounds) were extracted with TBME. After snap freezing the samples in a dry ice-ethanol bath, the organic layer was transferred to a clean tube and evaporated under a gentle stream of nitrogen gas. The dry extract was then reconstituted with 100μL acetonitrile and 5μL of the final extract was injected and separated on a C18 column with gradient elution, and analyzed with triple quadrupole mass spectrometry in positive-ion mode. The validated assay ranges from 50 to 5000ng/mL for dabrafenib and 0.5-50ng/mL for trametinib were linear, and correlation coefficient (r(2)) of 0.996 or better. At all concentrations of both analytes the biases were within ±15% of the nominal concentrations and precisions were ≤15%. All results were within the acceptance criteria of the latest US FDA guidance and EMA guidelines on method validation. Dabrafenib was found to degrade under the influence of light in different organic solvents and at least seven degradation products were detected. In conclusion, the described method to simultaneously quantify dabrafenib and trametinib in human plasma was successfully validated and applied for therapeutic drug monitoring in cancer patients treated with dabrafenib and trametinib. |
Databáze: | OpenAIRE |
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