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Absorption and Disposition of mavoglurant (AFQ056), a metabotropic glutamate receptor 5 antagonist (mGluR5), in healthy volunteers

Walles, Markus, Wolf, Thierry, Jin, Yi, Ritzau, Michael, Gschwind, Hans-Peter, Krauser, Joel, Woessner, Ralph, Ufer, Mike and Swart, Pieter Jacob (2013) Absorption and Disposition of mavoglurant (AFQ056), a metabotropic glutamate receptor 5 antagonist (mGluR5), in healthy volunteers. Drug Metabolism and Disposition, 41 (9). pp. 1626-1643.


Mavoglurant is a new candidate drug for the treatment of L-Dopa-induced dyskinesia in Parkinson`s disease and the Fragile X syndrome.
In the present work, the absorption, and disposition of [14C]-radiolabeled mavoglurant were investigated in four healthy male volunteers after a single oral dose of 200 mg. Total radioactivity was determined in plasma, urine and feces. Mavoglurant was quantified in plasma by LC-MS/MS and metabolite profiles were achieved in plasma and excreta by HPLC and radioactivity detection. The mavoglurant metabolite structures were elucidated by mass spectrometry, wet-chemical and enzymatic methods, NMR and comparison with reference compounds.
Cmax of mavoglurant and total radioactivity in plasma were reached at 2.5 and 3.6 hours, respectively, indicating moderately rapid onset of oral absorption. The Cmax of radioactivity (855 ng-eq/mL) was about 6-fold higher than that of mavoglurant (140 ng/mL) indicating moderately rapid formation and subsequent circulation of mavoglurant metabolite. The extent of absorption was ≥ 50% of the dose.
The biotransformation of mavoglurant involved two main pathways: A) hydroxylation of the tolyl-methyl group to a benzyl-alcohol metabolite (M7) and subsequentely to a benzoic acid metabolite (M6); B) hydroxylation of the phenyl ring leading to a hydroxylated metabolite (M3). The elimination of mavoglurant was fast and occured predominantly by oxidative metabolism. The subjects were mainly exposed to mavoglurant and five metabolites (M6, M15, M18, M14, M30) accounting combined for over 56% of 14C-AUC(0-72h). The remaining radioactivity was associated with minor metabolites. Inter-individual differences in pharmacokinetics and metabolism were moderate to high.
Drug related material was excreted mostly in feces (58.6% of dose) and urine (36.7% of dose) with an elimination half-life of 17.9 hours for total radioactivity and 12.0 hours for mavoglurant. After 7 days, the balance of excretion was almost complete (95.3% of dose).
In vitro incubation of mavoglurant in human liver microsomes and recombinant Cytochrome P450 isoenzymes confirmed major contributions of the CYP2C subfamily (CYP2C8, CYP2C9, CYP2C19) and CYP1A1 to oxidative metabolism of mavoglurant.

Item Type: Article
Keywords: AFQ056, Mavoglurant , human ADME, CYP
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46


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