Paul Severin1, Christopher Bailey2, Meng Chen1,3, Ashley Fisher1, Victoria Holmes2. 1. Covance Laboratories, Inc., 3301 Kinsman Blvd, Madison, WI 53704, USA. 2. Early Clinical Development, AstraZeneca, Da Vinci Building, Melbourn Science Park, Melbourn, Hertfordshire, SG8 6HB, UK. 3. Alexion Pharmaceuticals, 352 Knotter Dr, Cheshire, CT 06410, USA.
Abstract
AIM: 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. CONCLUSION: 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.
AIM: 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. CONCLUSION: 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: Alastair Greystoke; Nicola Steele; Hendrik-Tobias Arkenau; Fiona Blackhall; Noor Md Haris; Colin R Lindsay; Raffaele Califano; Mark Voskoboynik; Yvonne Summers; Karen So; Dana Ghiorghiu; Angela W Dymond; Stuart Hossack; Ruth Plummer; Emma Dean Journal: Br J Cancer Date: 2017-08-24 Impact factor: 7.640