Comparison of (19)F NMR and (14)C Measurements for the Assessment of ADME of BYL719 (Alpelisib) in Humans.
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James AD, Marvalin C, Luneau A, Meissner A, Camenisch G
Comparison of (19)F NMR and (14)C Measurements for the Assessment of ADME of BYL719 (Alpelisib) in Humans.
Drug Metab Dispos. 2017 Aug;45(8):900-907. doi: 10.1124/dmd.117.075424. Epub 2017 May 31.
- PubMed ID
- 28566285 [ View in PubMed]
- Abstract
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 (14)C or occasionally (3)H, 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 (19)F 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 (14)C human mass balance study conducted on Alpelisib (BYL719), a compound in late stage development at Novartis for the treatment of solid tumors. Quantitative (14)C data were used to cross-validate the data obtained by NMR. The data show that, using (19)F 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Alpelisib Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails - Drug Reactions
Reaction Details
