title: Absorption, distribution, metabolism, and excretion (ADME) of ¹⁴C-sonidegib (LDE225) in healthy volunteers.
abstract: OBJECTIVE
  The absorption, distribution, metabolism, and excretion of the hedgehog pathway inhibitor sonidegib (LDE225) were determined in healthy male subjects.
  
  
  METHODS
  Six subjects received a single oral dose of 800 mg ¹⁴C-sonidegib (74 kBq, 2.0 µCi) under fasting conditions. Blood, plasma, urine, and fecal samples were collected predose, postdose in-house (days 1-22), and during 24-h visits (weekly, days 29-43; biweekly, days 57-99). Radioactivity was determined in all samples using accelerator mass spectrometry (AMS). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine concentrations of sonidegib and its main circulating metabolite in plasma. Metabolite profiles and structures were determined in pooled plasma, urine, and fecal samples using high-performance LC-AMS and LC-MS/MS, respectively.
  
  
  RESULTS
  A single dose of ¹⁴C-sonidegib was well tolerated in healthy subjects. Unchanged sonidegib and total radioactivity reached peak concentration in plasma by 2 and 3 h, respectively, and demonstrated similarly long half-lives of 319 and 331 h, respectively. Absorbed sonidegib (estimated 6-7 %) was extensively distributed, and the approximate terminal volume of distribution was 2,500 L. Unchanged sonidegib and a metabolite resulting from amide hydrolysis were the major circulating components (36.4 and 15.4 % of radioactivity area under the curve, respectively). Absorbed sonidegib was eliminated predominantly through oxidative metabolism of the morpholine part and amide hydrolysis. Unabsorbed sonidegib was excreted through the feces. Metabolites in excreta accounted for 4.49 % of the dose (1.20 % in urine, 3.29 % in feces). The recovery of radioactivity in urine and feces was essentially complete (95.3 ± 1.93 % of the dose in five subjects; 56.9 % of the dose in one subject with incomplete feces collection suspected).
  
  
  CONCLUSIONS
  Sonidegib exhibited low absorption, was extensively distributed, and was slowly metabolized. Elimination of absorbed sonidegib occurred largely by oxidative and hydrolytic metabolism.
authors.affiliation: Drug Metabolism and Pharmacokinetics (DMPK), Novartis Institutes for BioMedical Research, Fabrikstrasse 14, 4002, Basel, Switzerland, markus.zollinger@novartis.com.
authors.forename: Markus
authors.initials: M
authors.lastname: Zollinger
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lozac'h
authors.forename: Eunju
authors.initials: E
authors.lastname: Hurh
authors.forename: Corinne
authors.initials: C
authors.lastname: Emotte
authors.forename: Hounayda
authors.initials: H
authors.lastname: Bauly
authors.forename: Piet
authors.initials: P
authors.lastname: Swart
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001565:Benzoates / Q000032:analysis / Q000737:chemistry / Q000652:urine; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000032:analysis / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D002250:Carbon Radioisotopes; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000032:analysis / Q000097:blood / Q000737:chemistry / Q000652:urine; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D008658:Inactivation, Metabolic; D007408:Intestinal Absorption; D008297:Male; D015394:Molecular Structure; D063806:Myalgia / Q000139:chemically induced / Q000503:physiopathology; D010084:Oxidation-Reduction; D011725:Pyridines / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D012720:Severity of Illness Index; D000072086:Smoothened Receptor; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D001713:Biphenyl Compounds; D002250:Carbon Radioisotopes; D020719:Glucuronides; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; C561435:sonidegib