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Absorption, distribution, metabolism, and excretion (ADME) of 14C-sonidegib (LDE225) in healthy volunteers

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Abstract

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.

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Acknowledgments

We thank Camille Perret, PhD (Drug Metabolism and Pharmacokinetics, Novartis, Basel, Switzerland, currently Hoffmann-La Roche), for her contributions to the study design; Albrecht Glaenzel, PhD (Isotope Laboratory, Novartis, Basel, Switzerland), Rolf Gerber, PhD, and Celine Decaudin (Technical Research and Development, Novartis, Basel, Switzerland) for preparing the radiolabeled drug substance and drug product; Julie Zalikowski and Ali Arjomand, PhD, from Accium BioSciences, Inc. (Seattle, WA, USA), for HPLC fractionations and AMS measurements; Ruud Lutgerink from Pharmaceutical Research Associates, Inc. (PRA, The Netherlands), for managing the clinical part of the study; Arnold Demailly and Xavier Homo (Drug Metabolism and Pharmacokinetics, Novartis, Basel, Switzerland) for supporting the metabolic and bioanalytical part of the study; and Stefan Peukert, PhD (Global Discovery Chemistry, Novartis, Cambridge, MA, USA), Matthias Kittelmann, PhD, Fabian Eggimann, Andreas Fredenhagen, PhD, and Juergen Kuehnoel (Global Discovery Chemistry, Novartis, Basel, Switzerland) for the synthesis of reference compounds. Medical editorial assistance was provided by Jillian Brechbiel, PhD, Karen Kaluza, PhD, and Karen Miller-Moslin, PhD; financial support for editorial assistance was provided by Novartis Pharmaceuticals Corporation.

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Authors and Affiliations

  1. Drug Metabolism and Pharmacokinetics (DMPK), Novartis Institutes for BioMedical Research, Fabrikstrasse 14, 4002, Basel, Switzerland

    Markus Zollinger, Frédéric Lozac’h, Corinne Emotte & Piet Swart

  2. Novartis Institutes for BioMedical Research, Cambridge, MA, USA

    Eunju Hurh

  3. Novartis Pharma AG, Basel, Switzerland

    Hounayda Bauly

Authors
  1. Markus Zollinger
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  2. Frédéric Lozac’h
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  3. Eunju Hurh
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  4. Corinne Emotte
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  5. Hounayda Bauly
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  6. Piet Swart
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Correspondence to Markus Zollinger.

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Zollinger, M., Lozac’h, F., Hurh, E. et al. Absorption, distribution, metabolism, and excretion (ADME) of 14C-sonidegib (LDE225) in healthy volunteers. Cancer Chemother Pharmacol 74, 63–75 (2014). https://doi.org/10.1007/s00280-014-2468-y

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  • DOI: https://doi.org/10.1007/s00280-014-2468-y

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