title: Absorption, distribution, metabolism, and excretion of [(14)C]BYL719 (alpelisib) in healthy male volunteers.
abstract: OBJECTIVE
  To determine the pharmacokinetics of the p110α-selective inhibitor alpelisib (BYL719) in humans, to identify metabolites in plasma and excreta, and to characterize pathways of biotransformation.
  
  
  METHODS
  Four healthy male volunteers received a single oral dose of [(14)C]-labeled alpelisib (400 mg, 2.78 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 radiometry and mass spectrometry. Complementary in vitro experiments characterized the hydrolytic, oxidative, and conjugative enzymes involved in metabolite formation.
  
  
  RESULTS
  Over 50 % of [(14)C] alpelisib was absorbed, with a T(max) of 2 h and an elimination half-life from plasma of 13.7 h. Over the first 12 h, exposure to alpelisib and the primary metabolite M4 was 67.9 and 26.7 % of total drug-related material in circulation, respectively. Mass balance was achieved, with 94.5 % of administered radioactivity recovered in excreta. In total, 38.2 % of alpelisib was excreted unchanged, while 39.5 % was excreted as M4. Based on the excreta pools analyzed, excretion occurred mainly via feces (79.8 % of administered dose); 13.1 % was excreted via urine. In vitro experiments showed that spontaneous and enzymatic hydrolysis contributed to M4 formation, while CYP3A4-mediated oxidation and UGT1A9-mediated glucuronidation formed minor metabolites. Alpelisib was well tolerated, and no new safety concerns were raised during this study.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics (DMPK), Novartis Institutes for BioMedical Research, Fabrikstrasse 14, 4002, Basel, Switzerland. alexander_david.james@novartis.com.
authors.forename: Alexander
authors.initials: A
authors.lastname: James
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Lars
authors.initials: L
authors.lastname: Blumenstein
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics (DMPK), Novartis Institutes for BioMedical Research, Fabrikstrasse 14, 4002, Basel, Switzerland.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Glaenzel
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics (DMPK), Novartis Institutes for BioMedical Research, Fabrikstrasse 14, 4002, Basel, Switzerland.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics (DMPK), Novartis Institutes for BioMedical Research, Fabrikstrasse 14, 4002, Basel, Switzerland.
authors.forename: Arnold
authors.initials: A
authors.lastname: Demailly
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics (DMPK), Novartis Institutes for BioMedical Research, Fabrikstrasse 14, 4002, Basel, Switzerland.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Jakab
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Regine
authors.initials: R
authors.lastname: Hansen
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Katharine
authors.initials: K
authors.lastname: Hazell
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Novartis Oncology, Paris, France.
authors.forename: Lucia
authors.initials: L
authors.lastname: Trandafir
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics (DMPK), Novartis Institutes for BioMedical Research, Fabrikstrasse 14, 4002, Basel, Switzerland.
authors.forename: Piet
authors.initials: P
authors.lastname: Swart
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D005243:Feces / Q000737:chemistry; D005500:Follow-Up Studies; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D007408:Intestinal Absorption; D066237:Intestinal Elimination; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D000081082:Phosphoinositide-3 Kinase Inhibitors; D065667:Renal Elimination; D013844:Thiazoles / Q000009:adverse effects / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014556:Urine / Q000737:chemistry; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013844:Thiazoles; C585539:Alpelisib
keywords: ADME; Alpelisib/BYL719; In vitro phenotyping; Mass balance; PI3K inhibitors