PT  - JOURNAL ARTICLE
AU  - James, Alexander David
AU  - Marvalin, Cyrille
AU  - Luneau, Alexandre
AU  - Meissner, Axel
AU  - Camenisch, Gian
TI  - Comparison of <sup>19</sup>F NMR and <sup>14</sup>C Measurements for the Assessment of ADME of BYL719 (Alpelisib) in Humans
AID  - 10.1124/dmd.117.075424
DP  - 2017 Aug 01
TA  - Drug Metabolism and Disposition
PG  - 900--907
VI  - 45
IP  - 8
4099  - http://dmd.aspetjournals.org/content/45/8/900.short
4100  - http://dmd.aspetjournals.org/content/45/8/900.full
SO  - Drug Metab Dispos2017 Aug 01; 45
AB  - 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 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 were 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.