Therapeutic Drug Monitoring of the new targeted anticancer agents imatinib, nilotinib, dasatinib, sunitinib, sorafenib and lapatinib by LC tandem mass spectrometry

• Published in: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Analytical technologies in the biomedical and life sciences, 2009-07, Vol.877 (22), p.1982-1996
• Main Authors: Haouala, A., Zanolari, B., Rochat, B., Montemurro, M., Zaman, K., Duchosal, M.A., Ris, H.B., Leyvraz, S., Widmer, N., Decosterd, L.A.
• Format: Article
• Language: English
• Subjects: Analysis; Analytical, structural and metabolic biochemistry; Anticancer targeted therapy; Antineoplastic Agents - blood; Antineoplastic Agents - therapeutic use; Benzamides; Benzenesulfonates - blood; Benzenesulfonates - therapeutic use; Biological and medical sciences; Chromatography, Liquid - methods; Dasatinib; Drug Monitoring - methods; Fundamental and applied biological sciences. Psychology; General pharmacology; Humans; Imatinib; Imatinib Mesylate; Indoles - blood; Indoles - therapeutic use; Lapatinib; LC–MS/MS; Medical sciences; Neoplasms - drug therapy; Niacinamide - analogs & derivatives; Nilotinib; Pharmacology. Drug treatments; Phenylurea Compounds; Piperazines - blood; Piperazines - therapeutic use; Plasma; Pyridines - blood; Pyridines - therapeutic use; Pyrimidines - blood; Pyrimidines - therapeutic use; Pyrroles - blood; Pyrroles - therapeutic use; Quinazolines - blood; Quinazolines - therapeutic use; Sorafenib; Sunitinib; Tandem Mass Spectrometry - methods; Thiazoles - blood; Thiazoles - therapeutic use; Tyrosine kinase inhibitors
• ISSN: 1570-0232; 1873-376X
• DOI: 10.1016/j.jchromb.2009.04.045

The treatment of some cancer patients has shifted from traditional, non-specific cytotoxic chemotherapy to chronic treatment with molecular targeted therapies. Imatinib mesylate, a selective inhibitor of tyrosine kinases (TKIs) is the most prominent example of this new era and has opened the way to the development of several additional TKIs, including sunitinib, nilotinib, dasatinib, sorafenib and lapatinib, in the treatment of various hematological malignancies and solid tumors. All these agents are characterized by an important inter-individual pharmacokinetic variability, are at risk for drug interactions, and are not devoid of toxicity. Additionally, they are administered for prolonged periods, anticipating the careful monitoring of their plasma exposure via Therapeutic Drug Monitoring (TDM) to be an important component of patients’ follow-up. We have developed a liquid chromatography–tandem mass spectrometry method (LC–MS/MS) requiring 100μL of plasma for the simultaneous determination of the six major TKIs currently in use. Plasma is purified by protein precipitation and the supernatant is diluted in ammonium formate 20mM (pH 4.0) 1:2. Reverse-phase chromatographic separation of TKIs is obtained using a gradient elution of 20mM ammonium formate pH 2.2 and acetonitrile containing 1% formic acid, followed by rinsing and re-equilibration to the initial solvent composition up to 20min. Analyte quantification, using matrix-matched calibration samples, is performed by electro-spray ionization–triple quadrupole mass spectrometry by selected reaction monitoring detection using the positive mode. The method was validated according to FDA recommendations, including assessment of extraction yield, matrix effects variability (