title: Quantification of 11 Therapeutic Kinase Inhibitors in Human Plasma for Therapeutic Drug Monitoring Using Liquid Chromatography Coupled With Tandem Mass Spectrometry.
abstract: A liquid chromatography/tandem mass spectrometry assay was developed to facilitate therapeutic drug monitoring (TDM) for 10 anticancer compounds (dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, and vemurafenib) and the active metabolite, N-desethyl-sunitinib.
  
  
  
  The TDM assay is based on reversed-phase chromatography coupled with tandem mass spectrometry in the positive ion mode using multiple reaction monitoring for analyte quantification. Stable isotopically labeled compounds were used as internal standards. The sample pretreatment consisted of protein precipitation with acetonitrile using a small plasma volume of 50 μL. The validation procedures were based on the guidelines on bioanalytical methods issued by the US Food and Drug Administration and were modified to fit the requirements of the clinical TDM environment.
  
  
  
  The method was validated over a linear range of 5.00-100 ng/mL for dasatinib, sunitinib, and N-desethyl-sunitinib; 50.0-1000 ng/mL for gefitinib and lapatinib; 125-2500 ng/mL for erlotinib, imatinib, and nilotinib; and 500-10,000 ng/mL for pazopanib, sorafenib, and vemurafenib. The results of the validation study demonstrated good intra-assay and interassay accuracy (bias <6.0%) and precision (12.2%) for all analytes.
  
  
  
  This newly validated method met the criteria for TDM and has successfully been applied to routine TDM service for tyrosine kinase inhibitors.
authors.affiliation: *Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital and MC Slotervaart, Louwesweg, Amsterdam, The Netherlands; and †Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg, Utrecht, The Netherlands.
authors.forename: Maikel
authors.initials: M
authors.lastname: Herbrink
authors.forename: Niels
authors.initials: N
authors.lastname: de Vries
authors.forename: Hilde
authors.initials: H
authors.lastname: Rosing
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Nuijen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000970:Antineoplastic Agents / Q000097:blood*; D002853:Chromatography, Liquid / Q000379:methods; D056148:Chromatography, Reverse-Phase / Q000379:methods; D016903:Drug Monitoring / Q000379:methods; D006801:Humans; D010949:Plasma / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000097:blood*; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors