PURPOSE: 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.