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Title Page Metabolism and Disposition of the Metabotropic Glutamate DMD Fast Forward. Published on June 17, 2013 as DOI: 10.1124/dmd.112.050716 DMD FastThis article Forward. has not been Published copyedited onand Juneformatted. 17, The 2013 final versionas doi:10.1124/dmd.112.050716 may differ from this version. DMD#50716 Title Page Metabolism and disposition of the metabotropic glutamate receptor 5 antagonist (mGluR5) mavoglurant (AFQ056) in healthy subjects Downloaded from Markus Walles, Thierry Wolf, Yi Jin, Michael Ritzau, Luc Alexis Leuthold, Joel Krauser, dmd.aspetjournals.org Hans-Peter Gschwind, David Carcache, Matthias Kittelmann, Magdalena Ocwieja, Mike Ufer, Ralph Woessner, Abhijit Chakraborty and Piet Swart at ASPET Journals on September 27, 2021 Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Basel Switzerland (M.W., T.W., Y.J., L.A.L., J. K. H.-P.G, R.W., A.C., P.S.) Analytical Sciences, Novartis Institutes for Biomedical Research, Basel, Switzerland (M.R.) Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Basel, Switzerland (M.K., D.C.) Clinical Science & Innovation Novartis Institutes for Biomedical Research, Basel, Switzerland (M.O.) Translational Medicine, Novartis Institutes for Biomedical Research, Basel, Switzerland (M.U.) 1 Copyright 2013 by the American Society for Pharmacology and Experimental Therapeutics. DMD Fast Forward. Published on June 17, 2013 as DOI: 10.1124/dmd.112.050716 This article has not been copyedited and formatted. The final version may differ from this version. DMD#50716 Running Title Page Running title: Mavoglurant: human ADME Corresponding author: Markus Walles Novartis Pharma AG NIBR//DMPK/BT Downloaded from Fabrikstrasse 14 WSJ-153.1.02.1 CH-4056 Basel, Switzerland dmd.aspetjournals.org Mobile: +41793497734 Fax: +41616968582 [email protected] at ASPET Journals on September 27, 2021 Manuscript statistics: Number of words in abstract ≤ 250: 243 Number of words in introduction ≤ 750: 386 Number of words in discussion ≤ 1500: 1472 Number of Figures: 9 Number of Tables: 6 Number of references ≤ 60: 18 Nonstandard abbreviations AFQ056: mavoglurant; AUC: Area under the concentration-time curve; AUC0-inf: AUC from time 0 to infinity; AUC0-tlast: AUC from time 0 to last measured time point tlast; ADME: Absorption, Distribution, Metabolism and Excretion; CV: coefficient of variation; 2 DMD Fast Forward. Published on June 17, 2013 as DOI: 10.1124/dmd.112.050716 This article has not been copyedited and formatted. The final version may differ from this version. DMD#50716 CYP: Cytochrome P450; HLM: human liver microsomes; HMBC: Heteronuclear multiple bond correlation NMR spectroscopy; HPLC: High performance liquid Chromatography; HSQC: Heteronuclear single quantum coherence NMR spectroscopy; kBq: kilo Becquerel; μCi: micro Curie; LC-MSE; Liquid chromatography coupled to mass spectrometry with collisional energy switching in collision cell; LID: L-dopa induced dyskinesia; LC-MS/MS: Liquid chromatography coupled to tandem mass spectrometry; LC-RAD-MS: HPLC coupled to offline radioactivity detection and mass spectrometry; mGLuR5: Metabotropic glutamate Downloaded from receptor 5; mSv: milli Sievert; NMR: Nuclear magnetic resonance spectroscopy; PD: Parkinson’s disease; ROESY: rotating-frame nuclear Overhauser effect correlation spectroscopy; SD: Standard deviation of mean; TOCSY: Total correlation NMR dmd.aspetjournals.org spectroscopy; t½: terminal half-life of elimination; at ASPET Journals on September 27, 2021 3 DMD Fast Forward. Published on June 17, 2013 as DOI: 10.1124/dmd.112.050716 This article has not been copyedited and formatted. The final version may differ from this version. DMD#50716 Abstract The disposition and biotransformation of 14C-radiolabeled mavoglurant were investigated in four healthy male subjects after a single oral dose of 200 mg. Blood, plasma, urine and feces collected over 7 days were analyzed for total radioactivity, mavoglurant was quantified in plasma by LC-MS/MS, and metabolite profiles were generated in plasma and excreta by HPLC and radioactivity detection. The chemical structures of mavoglurant metabolites were characterized by LC-MS/MS, wet-chemical and enzymatic methods, NMR spectroscopy and Downloaded from by comparison with reference compounds. Mavoglurant was safe and well tolerated in this study population. Mavoglurant absorption was ≥ 50% of dose reaching mean plasma Cmax dmd.aspetjournals.org values of 140 ng/mL (mavoglurant) and 855 ng-eq/mL (total radioactivity) at 2.5 and 3.6 hours, respectively. Thereafter, mavoglurant and total radioactivity concentrations declined with mean apparent half-lives of 12 and 18 hours, respectively. The elimination of mavoglurant occurred predominantly by oxidative metabolism involving primarily: at ASPET Journals on September 27, 2021 A) oxidation of the tolyl-methyl group to a benzyl-alcohol metabolite (M7) and subsequently to a benzoic acid metabolite (M6), and B) oxidation of the phenyl-ring leading to a hydroxylated metabolite (M3). The subjects were mainly exposed to mavoglurant and seven 14 main metabolites, which combined accounted for 60% of C-AUC0-72h. The primary steps of mavoglurant metabolism observed in vivo could partially be reproduced in vitro in incubations with human liver microsomes and recombinant CYP enzymes. After 7 days, the mean balance of total radioactivity excretion was almost complete (95.3% of dose) with 36.7% recovered in urine and 58.6% in feces. 4 DMD Fast Forward. Published on June 17, 2013 as DOI: 10.1124/dmd.112.050716 This article has not been copyedited and formatted. The final version may differ from this version. DMD#50716 Introduction Mavoglurant (AFQ056) is a non-competitive antagonist at the metabotropic glutamate receptor 5 (mGluR5) and is currently under clinical development for the treatment of Parkinson’s disease associated levodopa-induced dyskinesia (PD-LID). Levodopa has been used for many years as an effective treatment of Parkinson’s disease (PD) and still remains the gold standard of care (Hauser, 2009). However, its clinical use is hampered by the high incidence of dyskinesia that affects approximately 40% of patients with Parkinson’s disease Downloaded from after four to six years of treatment with levodopa (Ahlskoog and Muenter, 2001). A dysregulation of both dopamine and glutamatergic transmission has been proposed to contribute to the development of PD-LID (Chase and Oh, 2000). Because an inhibition of dmd.aspetjournals.org mGluR5 was shown to alleviate dyskinetic symptoms and reverse movement disorders in rat models of PD (Rylander et al., 2009; Mela et al., 2007), the non-competitive mGluR5 antagonist mavoglurant is expected to exhibit antidyskinetic effects as it has already been at ASPET Journals on September 27, 2021 demonstrated in two monkey studies (Grégoire et al., 2011; Morin et al., 2010). Most importantly, in two recent patient studies mavoglurant was shown to be effective in the treatment of moderate to severe PD-LID (Berg et al., 2011). Another indication of mavoglurant is the treatment of fragile X syndrome, which is caused by expansion of a CGG trinucleotide repeat in the 5´untranslated region of the fragile X mental retardation 1 (FMR1) gene. The fragile X syndrome is associated with intellectual disability and behavioral problems in children as well as adults (Levenga et al., 2011). In a recent study it was shown that therapeutic blockage of mGLuR5 by mavoglurant can improve the behavioral symptoms in male adults with fragile X and that this improvement is predicted by full methylation at the FMR1 promoter (Jacquemont et al., 2011). Therefore mavoglurant has the potential to provide a novel therapeutic approach for both aforementioned indications and, as a result, a good understanding of the absorption, distribution, metabolism and excretion (ADME) properties 5 DMD Fast Forward. Published on June 17, 2013 as DOI: 10.1124/dmd.112.050716 This article has not been copyedited and formatted. The final version may differ from this version. DMD#50716 of the drug is necessary for successful clinical development and safe treatment of patients. In this article, we present the results of an ADME study in healthy male subjects after a single oral dose of 200 mg 14C-radiolabeled mavoglurant. In addition to this human ADME study, the in vitro metabolism of [14C]mavoglurant was investigated in incubations with human liver microsomes and various recombinant CYP enzymes. Downloaded from dmd.aspetjournals.org at ASPET Journals on September 27, 2021 6 DMD Fast Forward. Published on June 17, 2013 as DOI: 10.1124/dmd.112.050716 This article has not been copyedited and formatted. The final version may differ from this version. DMD#50716 Materials and Methods Study drug. [14C]Mavoglurant, (IUPAC name: (3aR,4S,7aR)-4-Hydroxy-4-(3- [14C]methylphenyl)ethynyl-octahydro-indole-1-carboxylic acid methyl ester) with a specific radioactivity of 16.1 kBq/mg (0.435 µCi/mg) and a radiochemical purity of > 99% was synthesized by the Isotope Laboratory of Novartis (Basel, Switzerland). For the in vitro experiments, [14C]mavoglurant with a specific radioactivity of 5.62 MBq/mg (152 µCi/mg) and a radiochemical purity of > 96% was used. The chemical structure of the compound and Downloaded from the position of the radiolabel are shown in Figure 1. Chemicals and standards. Authentic standards of the metabolites M1, M2, M3, M6, M7, 13 dmd.aspetjournals.org M14, M15, M16, M30, M31, non-radiolabeled mavoglurant and [ CD3]mavoglurant (used as internal standard for the quantitation
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