Metabolism and Disposition of the Metabotropic Glutamate Receptor 5 Antagonist (mGluR5) Mavoglurant (AFQ056) in Healthy Subjects

Abstract

The disposition and biotransformation of 14 C-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 liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), and metabolite profiles were generated in plasma and excreta by high-performance liquid chromatography (HPLC) and radioactivity detection. The chemical structures of mavoglurant metabolites were characterized by LC-MS/MS, wetchemical and enzymatic methods, NMR spectroscopy, and comparison with reference compounds. Mavoglurant was safe and well tolerated in this study population. Mavoglurant absorption was ‡50% of dose reaching mean plasma C max 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 1) oxidation of the tolyl-methyl group to a benzyl-alcohol metabolite (M7) and subsequently to a benzoic acid metabolite (M6), and 2) oxidation of the phenyl-ring leading to a hydroxylated metabolite (M3). The subjects were mainly exposed to mavoglurant and seven main metabolites, which combined accounted for 60% of 14 C-AUC 0-72 h (area under the concentration-time curve from time 0 to infinity). The primary steps of mavoglurant metabolism observed in vivo could partially be reproduced in vitro in incubations with human liver microsomes and recombinant cytochrome P450 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.

The selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056) reduces the incidence of reflux episodes in dogs and patients with moderate to severe gastroesophageal reflux disease

“…Pharmacokinetic data of both mavoglurant and baclofen was essentially in line with data from earlier clinical studies . In addition, single, oral doses of 50 mg and 400 mg mavoglurant were safe and tolerated in this study, primarily given the similar incidence of AEs with mavoglurant and placebo and the lack of any relevant changes in laboratory, vital signs, or ECG data.…”

Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation

“…Both compounds are structurally similar disubstituted alkynes, a motif that has been exploited for the design of several other highly optimized mGlu 5 NAM compounds. 4,5 While results from clinical studies have been reported with nonalkyne based mGlu 5 NAMs such as 3 (fenobam), 17,18 4 (AZD9272), 19,20 and 5 (AZD2066), 19,20 the most highly studied and advanced clinical compounds are three alkyne mGlu 5 NAMs: 6 (mavoglurant), 14,21−25 7 (basimglurant), 26−29 and 8 (dipraglurant) 30,31 (Figure 1). Still, failures to reach primary clinical end points with 6 (14,22,23) and 7 (28) point to the continued need for highly optimized mGlu 5 NAMs.…”

“…35 This toxicity was believed to be linked to the reactivity of the alkyne based on metabolic studies that revealed extensive glutathione conjugation. 35 While this type of biotransformation does not always manifest in humans with alkyne-containing compounds, 25,27 many research groups have sought to design novel mGlu 5 NAMs that are outside of this chemotype. 4,5 We have actively pursued a variety of approaches toward that end over the past decade.…”

Differences in the In Vivo and In Vitro Metabolism of Imrecoxib in Humans: Formation of the Rate-Limiting Aldehyde Intermediate

“…Drugs containing the benzylic carbon motif are prone to be oxidized to its corresponding benzylic alcohol (Mamidi et al, 2014;Ryu et al, 2014) and/or further to the end-product carboxylic acids in vivo (Hvenegaard et al, 2012;Walles et al, 2013;Pozo et al, 2015). It is recognized that there is an aldehyde intermediate in metabolic processing from alcohol to carboxylic acid, and some in vitro trapping tests with methoxyamine or semicarbazide also provided convincing evidence (Li et al, 2014;Inoue et al, 2015;Liu et al, 2015).…”