title: Bioanalysis of alectinib and metabolite M4 in human plasma, cross-validation and impact on PK assessment.
abstract: BACKGROUND
  Alectinib is a novel anaplastic lymphoma kinase (ALK) inhibitor for treatment of patients with ALK-positive non-small-cell lung cancer who have progressed on or are intolerant to crizotinib. To support clinical development, concentrations of alectinib and metabolite M4 were determined in plasma from patients and healthy subjects.
  
  
  METHODS
  LC-MS/MS methods were developed and validated in two different laboratories: Chugai used separate assays for alectinib and M4 in a pivotal Phase I/II study while Roche established a simultaneous assay for both analytes for another pivotal study and all other studies.
  
  
  CONCLUSIONS
  Cross-validation assessment revealed a bias between the two bioanalytical laboratories, which was confirmed with the clinical PK data between both pivotal studies using the different bioanalytical methods.
authors.affiliation: Roche Pharmaceutical Research & Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Katja
authors.initials: K
authors.lastname: Heinig
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara Kamakura Kanagawa, 247-8530 Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Miya
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara Kamakura Kanagawa, 247-8530 Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kamei
authors.affiliation: Roche Pharmaceutical Research & Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Guerini
authors.affiliation: Roche Pharmaceutical Research & Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Fraier
authors.affiliation: Roche Pharmaceutical Research & Early Development, Roche Innovation Center New York, F. Hoffmann-La Roche Ltd, 430 East 29th Street, New York, NY 10016, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.affiliation: Roche Pharmaceutical Research & Early Development, Roche Innovation Center New York, F. Hoffmann-La Roche Ltd, 430 East 29th Street, New York, NY 10016, USA.
authors.forename: Surendra
authors.initials: S
authors.lastname: Bansal
authors.affiliation: Roche Pharmaceutical Research & Early Development, Roche Innovation Center New York, F. Hoffmann-La Roche Ltd, 430 East 29th Street, New York, NY 10016, USA.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Morcos
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002227:Carbazoles / Q000097:blood* / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology; D002851:Chromatography, High Pressure Liquid / Q000295:instrumentation / Q000379:methods*; D004867:Equipment Design; D006801:Humans; D057230:Limit of Detection; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology; D010880:Piperidines / Q000097:blood* / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000097:blood* / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D053719:Tandem Mass Spectrometry / Q000295:instrumentation / Q000379:methods*
chemical_list: D002227:Carbazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C582670:alectinib
keywords: Alecensa®; LC–MS/MS; alectinib; anaplastic lymphoma kinase; column switching; cross-validation; matrix effect; non-small-cell lung cancer; phospholipids; plasma