title: Determination of selumetinib, N-desmethyl selumetinib and selumetinib amide in human biological samples by LC-MS/MS.
abstract: OBJECTIVE
  Selumetinib is an inhibitor of MEK1/2 in Phase III development that has activity in multiple tumor types. Validated bioanalytical methods were required to quantitate selumetinib and its N-desmethyl and amide metabolites in a variety of human biological matrices. Methodology & results: LC-MS/MS assays were developed and validated that demonstrated acceptable precision, accuracy and selectivity for selumetinib and the two metabolites in human plasma, urine, blood dialysate and plasma ultrafiltrate. Incurred sample re-analysis was acceptable and issues observed in plasma with the amide metabolite, due to potential instability, were addressed.
  
  
  CONCLUSIONS
  Robust and sensitive LC-MS/MS assays for the quantification of selumetinib and two of its metabolites were validated in human biological matrices and are being used to support the clinical development program.
authors: Covance Laboratories, Inc., 3301 Kinsman Blvd, Madison, WI 53704, USA.
authors: Paul
authors: P
authors: Severin
authors: Early Clinical Development, AstraZeneca, Da Vinci Building, Melbourn Science Park, Melbourn, Hertfordshire, SG8 6HB, UK.
authors: Christopher
authors: C
authors: Bailey
authors: Covance Laboratories, Inc., 3301 Kinsman Blvd, Madison, WI 53704, USA.|Alexion Pharmaceuticals, 352 Knotter Dr, Cheshire, CT 06410, USA.
authors: Meng
authors: M
authors: Chen
authors: Covance Laboratories, Inc., 3301 Kinsman Blvd, Madison, WI 53704, USA.
authors: Ashley
authors: A
authors: Fisher
authors: Early Clinical Development, AstraZeneca, Da Vinci Building, Melbourn Science Park, Melbourn, Hertfordshire, SG8 6HB, UK.
authors: Victoria
authors: V
authors: Holmes
mesh_terms: D000577:Amides / Q000097:blood / Q000378:metabolism / Q000652:urine; D001562:Benzimidazoles / Q000097:blood* / Q000378:metabolism / Q000652:urine*; D002853:Chromatography, Liquid / Q000379:methods; D016903:Drug Monitoring / Q000379:methods; D006801:Humans; D057230:Limit of Detection; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000097:blood* / Q000378:metabolism / Q000652:urine*; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: C517975:AZD 6244; D000577:Amides; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; C482128:MAP2K2 protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2
keywords: LC–MS/MS; blood dialysate; clinical; oncology; plasma; plasma ultrafiltrate; selumetinib; urine; validation