Metabolism of the MEK1/2 Inhibitor Pimasertib Involves a Novel Conjugation with Phospho-Ethanolamine in Patients with Solid Tumors

Pimasertib (AS703026 or MSC1936369B) is a selective inhibitor of MEK1/2, the mitogen-activated protein kinase (MAPK) signaling pathway, which is often dysregulated in cancer cells. Pimasertib has shown potent preclinical anti tumor activity and its clinical activity is being investigated in various tumor types. In this phase I study, the disposition and biotransformation of 14 C-radiolabeled pimasertib was investigated in six patients with locally advanced or metastatic solid tumors (NCT 01713036). Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) and radiodetection techniques were used to investigate the profiles and structures of metabolites in plasma, urine and feces after a single oral dose of 14 C-pimasertib. A total of 14 different phase I and II metabolites of 14 C-pimasertib were detected, which were principally generated through oxidations and conjugations (direct and indirect); but other reactions included isomerization, N-dealkylation, de-amination and de-iodination to form minor metabolites. Two major metabolites (>10% of total drug related material), M554 and M445, were identified in plasma and urine. In feces, M445 was the primary metabolite with only trace amounts of M554 excreted. All other metabolites, including enantiomers of M445 and pimasertib, were detected to a lesser extent (