Determination of selumetinib, N-desmethyl selumetinib and selumetinib amide in human biological samples by LC–MS/MS

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.