title: Quantification of sunitinib and N-desethyl sunitinib in human EDTA plasma by liquid chromatography coupled with electrospray ionization tandem mass spectrometry: validation and application in routine therapeutic drug monitoring.
abstract: BACKGROUND
  Given the low therapeutic index, the large interindividual variability in systemic exposure and the positive exposure-efficacy relationship of sunitinib, there is a rationale for therapeutic drug monitoring (TDM) of sunitinib. To support TDM, a method for determination of sunitinib and its active metabolite (N-desethyl sunitinib) has been developed and validated.
  
  
  METHODS
  For determination of sunitinib and N-desethyl sunitinib in human EDTA plasma samples, high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was used. Validation experiments according to Food and Drug Administration guidelines were performed. In addition, the results of 25 analytical runs with 58 patient samples using 8 calibrators and 3 levels of quality control (QC) samples per analysis were compared with the results of analyses using only 3 calibrators and 1 QC sample to accelerate sample turnaround time. The method comparison experiment was performed according to international guidelines.
  
  
  RESULTS
  The HPLC-MS/MS method was validated over a linear range from 2.5 to 500 ng/mL using 50 μL plasma volumes, with good intra- and interassay accuracy and precision. In addition, the mean of the absolute differences between the compared methods was only -0.66 ng/mL (mean of relative differences, -0.85%), which is not a clinically relevant difference.
  
  
  CONCLUSIONS
  This method has been applied successfully for routine TDM purposes for patients treated with sunitinib. Moreover, reliable results with a rapid turnaround time were obtained when performing a short analytical run containing only 3 calibrators and 1 QC sample.
authors.affiliation: Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands. n.lankheet@hotmail.com
authors.forename: Nienke A G
authors.initials: NA
authors.lastname: Lankheet
authors.forename: N
authors.initials: N
authors.lastname: Steeghs
authors.forename: H
authors.initials: H
authors.lastname: Rosing
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: A D R
authors.initials: AD
authors.lastname: Huitema
mesh_terms: D002853:Chromatography, Liquid / Q000592:standards; D016903:Drug Monitoring / Q000592:standards*; D004492:Edetic Acid / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000378:metabolism*; D011758:Pyrroles / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000592:standards*; D000077210:Sunitinib; D053719:Tandem Mass Spectrometry / Q000592:standards*
chemical_list: D007211:Indoles; D011758:Pyrroles; D004492:Edetic Acid; D000077210:Sunitinib