Single- and Multiple-Dose Pharmacokinetics, Safety, and Tolerability of the Selective α7 Neuronal Nicotinic Receptor Agonist, ABT-107, in Healthy Human Volunteers
Abstract
ABT-107 is a potent, selective α7 nicotinic receptor agonist under development for treatment of Alzheimer's disease and cognitive deficits associated with schizophrenia. The pharmacokinetics, safety, and tolerability of escalating single oral doses (1, 3, 10, 30, 60, 80, and 100 mg; double-blind, placebo-controlled, randomized, incomplete crossover design) and multiple oral doses (2, 6, and 15 mg once daily for 7 days; double-blind, placebo-controlled, randomized, parallel-group design) of ABT-107 were evaluated. Additionally, effect of food on ABT-107 pharmacokinetics (20-mg single dose) was evaluated using an open-label, 2-period, fasting and nonfasting, randomized, complete crossover design. ABT-107 exhibited nonlinear (more than dose-proportional) pharmacokinetics. ABT-107 half-life ranged from 7 to 10 hours, and steady state was achieved by day 6 of dosing. Food did not have a clinically meaningful effect on ABT-107 exposure. ABT-107 was safe and well tolerated over the tested dose range. The most frequently reported adverse events were nausea, headache, and tremor following single dosing and somnolence following multiple dosing. The pharmacokinetics, safety, and tolerability profiles of ABT-107 pose it as a good candidate for further development.
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ABT-107 has low incidence of side effects at varying doses in patients.
“ABT-107 [5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole; structure in Bitner et al., 2010] is a selective agonist with high affinity at a7 nAChRs that has been characterized as a cognitive enhancer in animal models of Alzheimer's disease and has low incidence of side effects at varying doses in patients (Bitner et al., 2010;Malysz et al., 2010;Othman et al., 2011).”
From Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors (2014) · cites this paper as Othman et al., 2011
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- Authors
- Othman, A. A., Lenz, R. A., Zhang, J., Li, J., Awni, W. M., & Dutta, S.
- Affiliations
- Abbott (United States) (US)
- Corresponding author
- Othman, Ahmed A.
- Venue
- The Journal of Clinical Pharmacology
- Publisher
- Wiley
- Published
- 2011-04
- Volume
- 51
- Issue
- 4
- Pages
- 512-526
- ISSN
- 0021-9754 (ISSN-L)
- 0091-2700
- OpenAlex
- W2079313511
- Cited by
- 24
- References
- 33
- Citations by year
- 2021: 1 · 2019: 1 · 2018: 1 · 2017: 2 · 2015: 3 · 2014: 7 · 2013: 4 · 2012: 3
- FWCI
- 1.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- α7 nicotinic acetylcholine receptor agonist, pharmacokinetics, nonlinear pharmacokinetics, food effect, safety and tolerability, Alzheimer's disease, schizophrenia, cognitive impairment, healthy volunteers
- MeSH terms
- Adult, Dosage Forms, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Fasting, Female, Half-Life, Humans, Indoles, Male, Placebos, Quinuclidines, Receptors, Nicotinic, Cross-Over Studies, Nicotinic Agonists, alpha7 Nicotinic Acetylcholine Receptor
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