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.

Keywords:

Papers of special note have been highlighted as: •• of considerable interest

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Vol. 8, No. 18

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Published online 15 August 2016

Published in print September 2016

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Keywords

Acknowledgements

The authors would like to thank LGC for the development and validation of initial methods for the analysis of selumetinib, N-desmethyl-sel and sel-amide in human plasma and for the validation and supply of long-term stability data of selumetinib, N-desmethyl-sel and sel-amide in plasma stored at nominal temperatures of -20 or -80°C, as well as the primary stock solutions.

Financial & competing interests disclosure

This research was funded by AstraZeneca. P Severin is a current employee, and M Chen and A Fisher are former employees of Covance Laboratories, Inc., the company that developed and validated the methodologies in partnership with AstraZeneca. Christopher Bailey and Victoria Holmes are employees of AstraZeneca and hold AstraZeneca stock. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

The authors thank Kerry Acheson PhD CMPP™, from iMed Comms, an Ashfield Company, part of UDG Healthcare plc, who provided medical writing assistance funded by AstraZeneca.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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