1521-009X/46/4/429–439$35.00 https://doi.org/10.1124/dmd.117.077511 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 46:429–439, April 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Metabolism and Disposition of a Novel Selective a7 Neuronal Acetylcholine Receptor Agonist ABT-126 in Humans: Characterization of the Major Roles for Flavin-Containing Monooxygenases and UDP-Glucuronosyl Transferase 1A4 and 2B10 in Catalysis s Hong Liu, 1 David M. Stresser, Melissa J. Michmerhuizen, Xiaofeng Li, Ahmed A. Othman, Aimee D. Reed, Michael R. Schrimpf, Jens Sydor, and Anthony J. Lee 2 Bioanalysis and Biotransformation (H.L., M.J.M., J.S., A.J.L.), DMPK and Translational Modeling (D.M.S., X.L.), Process Chemistry (A.D.R.), Discovery Chemistry and Technology (M.R.S.), and Clinical Pharmacology and Pharmacometrics (A.A.O.), Research and Development, AbbVie, North Chicago, Illinois Received July 12, 2017; accepted January 11, 2018 ABSTRACT Mass balance, metabolism, and excretion of ABT-126, an a7 neuronal acetylcholine receptor agonist, were characterized in healthy male subjects (n = 4) after a single 100-mg (100 mCi) oral dose. The total recovery of the administered radioactivity was 94.0% (62.09%), with 81.5% (610.2%) in urine and 12.4% (69.3%) in feces. Metabolite profiling indicated that ABT-126 had been extensively metabolized, with 6.6% of the dose remaining as unchanged parent drug in urine. Parent drug accounted for 12.2% of the administered radioactivity in feces. The primary metabolic transformations of ABT-126 involved aza-adamantane N-oxidation (M1, 50.3% in urine) and aza-adamantane N-glucuronidation (M11, 19.9% in urine). M1 and M11 were also major circulating metabolites, accounting for 32.6% and 36.6% of the drug-related material in plasma, respectively. These results demonstrated that ABT-126 is eliminated primarily by hepatic metabolism, followed by urinary excretion. Enzymatic studies suggested that M1 formation is mediated primarily by human liver flavin-containing monooxygenase (FMO)3 and, to a lesser extent, by human kidney FMO1; M11 is generated mainly by human uridine 59-diphospho-glucuronosyltransferase (UGT) 1A4, whereas UGT 2B10 also contributes to ABT-126 glucuronidation. Species-dependent formation of M11 was observed in hepatocytes; M11 was formed in human and monkey hepatocytes, but not in rat and dog hepatocytes, suggesting that monkeys constitute an appropriate model for pre- dicting the fate of compounds undergoing significant N-glucuronida- tion. M1 and M11 are not expected to have clinically relevant on- or off-target pharmacologic activities. In summary, this study charac- terized ABT-126 metabolites in the circulation and excreta and the primary elimination pathways of ABT-126 in humans. Introduction Alzheimer disease (AD) is a chronic neurodegenerative disease and the most common cause of dementia. As of 2016, an estimated 5.4 million Americans have AD (Alzheimer’s Association, 2016). The few available treatments for AD [acetylcholine esterase inhibitors and N-methyl-D- aspartate receptor antagonists] provide temporary improvement in cognition, but none of them slows or stops the damage of neurons that cause symptoms of AD. There is a clear medical need for new therapy to treat this disease. The a7 neuronal acetylcholine receptors (nAChRs) are acetylcholine- gated cation channels that are localized on the brain regions critical to the synaptic plasticity underlying learning and memory. Activation of a7 nAChRs can cause the release of neurotransmitters (GABA, acetylcho- line [ACh], and glutamate) important for cognition (Lendvai et al., 2013). Several studies suggest that a7 nAChR plays a significant role in the development of AD pathology (Gotti and Clementi, 2004; Roncarati et al., 2009). The a7 nAChR agonist under development by EnVivo (EVP-6124) has shown the potential in the treatment of AD (Deardorff et al., 2015). ABT-126 is a potent and selective a7 nAChR agonist with high binding affinity (K i = 12–14 nM) to a7 nAChRs (human, rat, or mouse cortex) (Gault et al., 2016). ABT-126 shows significantly less affinity (.140-fold) toward other nAChR subtypes and muscarinic receptor and therefore is expected to eliminate the dose-limiting toxicity associated with acetylcholine esterase inhibitors. ABT-126 exhibits a preclinical efficacy profile across multiple cognitive domains of relevance to AD. ABT-126 was evaluated in single-dose and multiple dose phase 1 studies, and doses up to 150 mg once daily or up to 40 mg twice a day were generally well tolerated (AbbVie internal data). The results of a 1 Current affiliation: Novartis Institutes for BioMedical Research Pharmacoki- netic Sciences, Cambridge, Massachusetts; 2 Seattle Genetics, Bothell, WA. https://doi.org/10.1124/dmd.117.077511. s This article has supplemental material available at dmd.aspetjournals.org. ABBREVIATIONS: AD, Alzheimer disease; AUC, area under the curve; FMO, flavin-containing monooxygenase; HKM, human kidney microsome; HLM, human liver microsome; HPLC, high-performance liquid chromatography; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LLOQ, lower limit of quantitation; LSC, liquid scintillation counting; nAChRs, neuronal acetylcholine receptors; P450, cytochrome P450; PD, pharmacodynamic; PK, pharmacokinetic; SPE, solid-phase extraction; UGT, uridine 59-diphospho-glucuronosyltransferase. 429 http://dmd.aspetjournals.org/content/suppl/2018/01/18/dmd.117.077511.DC1 Supplemental material to this article can be found at: at ASPET Journals on May 5, 2020 dmd.aspetjournals.org Downloaded from