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Absorption, distribution, metabolism, and excretion of [14C]BYL719 (alpelisib) in healthy male volunteers

James, Alexander David, Blumenstein, Lars, Glaenzel, Ulrike, Jin, Yi, Demailly, Arnold, Jakab, Annamaria, Hansen, Regine, Hazell, Katharine Mary, Mehta, Anuradha, Trandafir, Lucia, Coughlin, Christina and Swart, Pieter Jacob (2015) Absorption, distribution, metabolism, and excretion of [14C]BYL719 (alpelisib) in healthy male volunteers. Cancer Chemotherapy and Pharmacology, 76. pp. 751-760.


This study aimed to determine the pharmacokinetics of the p110α-selective inhibitor alpelisib (BYL719) in human subjects, to identify metabolites in plasma and excreta, and to characterize pathways of biotransformation.
Four healthy, male volunteers received a single, oral dose of [14C]-labeled alpelisib (400 mg, 2.70 MBq). Blood, urine, and feces samples were collected throughout the study. Total radioactivity was measured by liquid scintillation counting, and metabolites were quantified and identified by HPLC–radiometry and HPLC–MS/MS. Complementary in vitro experiments characterized the hydrolytic, oxidative, and conjugative enzymes involved in metabolite formation.
Over 50% of [14C]-alpelisib was absorbed, with a Tmax of 2 hours. The elimination half-life of alpelisib from plasma was 13.7 hours. Exposure to alpelisib was 67.9% of total dose over the first 12 hours, and 26.7% to the primary metabolite M4. Mass balance was achieved, with 94.2% of administered radioactivity recovered in urine and feces. In total, 37.8% of alpelisib was excreted unchanged, while 39.1% was excreted as M4. Excretion occurred mainly via feces (78.8% of administered dose) and to a lesser extent via urine (13.1%). In vitro experiments showed that spontaneous and enzymatic hydrolysis contributed to M4 formation, while CPY3A4-mediated oxidation and UGT1A9-mediated glucuronidation formed minor metabolites. Alpelisib was well tolerated and no new safety concerns were raised during the study.
Alpelisib was rapidly absorbed and cleared by multiple metabolic pathways; the primary metabolite M4 is pharmacologically inactive. Alpelisib has limited potential for drug-drug interactions, and is therefore a promising candidate for combination therapy

Item Type: Article
Keywords: ADME; mass balance; PI3K inhibitors; alpelisib/BYL719; alpelisib; in vitro phenotyping
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45