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Comparison of 19F-NMR and 14C measurements for the assessment of ADME of BYL719 (Alpelisib) in humans

James, Alexander David, Marvalin, Cyrille, Luneau, Alexandre, Meissner, Axel and Camenisch, Gian P. (2017) Comparison of 19F-NMR and 14C measurements for the assessment of ADME of BYL719 (Alpelisib) in humans. Drug metabolism and disposition, 45. pp. 900-907. ISSN 1521-009X


The human mass balance study is the definitive study for the assessment of absorption, distribution, metabolism and excretion (ADME) properties of a new chemical entity (NCE) in humans. Traditionally this has been carried out by the administration of radiolabeled drug substances, typically 14C or occasionally 3H, as detection methods for these isotopes allow the absolute quantification of drug related material (DRM) in blood, plasma and excreta. Coupled with the use of analytical techniques such as liquid chromatography-mass spectrometry, a picture of the metabolic fate of a compound can be elucidated. In this study we demonstrate the capabilities of 19F-nuclear magnetic resonance (NMR) spectroscopy, applied as an alternative to radiolabeling, for the determination of mass balance and for metabolite profiling of an orally administered fluorinated drug. To demonstrate the capabilities of NMR, the study was conducted on remaining samples from a 14C human mass balance study conducted on Alpelisib (BYL719), a compound in late stage development at Novartis for the treatment of solid tumors. Quantitative 14C data was used to cross-validate the data obtained by NMR. The data show that, using 19F-NMR, comparable data can be obtained for key human ADME endpoints including mass balance, total DRM determination in plasma and metabolite profiling and identification in plasma and excreta. Potential scenarios where NMR could be employed as an alternative to radiolabeling for the conduct of an early human ADME study are discussed

Item Type: Article
Date Deposited: 03 Aug 2017 00:45
Last Modified: 03 Aug 2017 00:45