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Safety, Tolerability, and Pharmacokinetics of Repeated Oral Pitchford et al. BMC Pharmacology and Toxicology (2020) 21:3 https://doi.org/10.1186/s40360-020-0382-y RESEARCH ARTICLE Open Access Safety, tolerability, and pharmacokinetics of repeated oral doses of 2- hydroxybenzylamine acetate in healthy volunteers: a double-blind, randomized, placebo-controlled clinical trial Lisa M. Pitchford1,2* , Patricia M. Driver3, John C. Fuller Jr1, Wendell S. Akers4,5, Naji N. Abumrad6, Venkataraman Amarnath3, Ginger L. Milne3, Sheau-Chiann Chen7, Fei Ye7, L. Jackson Roberts II3, M. Benjamin Shoemaker8, John A. Oates3,5ˆ, John A. Rathmacher1,9 and Olivier Boutaud5 Abstract Background: 2-Hydroxybenzylamine (2-HOBA) is a selective dicarbonyl electrophile scavenger being developed as a nutritional supplement to help protect against the development of conditions associated with dicarbonyl electrophile formation, such as the cognitive decline observed with Mild Cognitive Impairment or Alzheimer’sdisease. Methods: This study evaluated the safety, tolerability, and pharmacokinetics of repeated oral doses of 2-HOBA acetate (500 or 750 mg) administered to healthy volunteers every eight hours for two weeks. The effects of 2-HOBA on cyclooxygenase function and cerebrospinal fluid penetrance of 2-HOBA were also investigated. Results: Repeated oral administration of 2-HOBA was found to be safe and well-tolerated up to 750 mg TID for 15 days. 2-HOBA was absorbed within 2 h of administration, had a half-life of 2.10–3.27 h, and an accumulation ratio of 1.38–1.52. 2-HOBA did not interfere with cyclooxygenase function and was found to be present in cerebrospinal fluid 90 min after dosing. Conclusions: Repeated oral administration of 2-HOBA was found to be safe and well-tolerated. These results support continued development of 2-HOBA as a nutritional supplement. Trial registration: Studies are registered at ClinicalTrials.gov (NCT03555682 Registered 13 June 2018, NCT03554096 Registered 12 June 18). Keywords: Safety, Pharmacokinetics, Humans, Salicylamine, γ-Ketoaldehydes Background isolevuglandin-protein adducts have been observed in pa- Reactive dicarbonyl electrophiles, such as isolevuglandin, tients with a variety of clinical conditions, including, but form in response to inflammation and oxidative stress, and not limited to, Alzheimer’sdisease[3], atherosclerosis [4], have been implicated in the development and progression hypertension [5], atrial fibrillation [6], and liver disease [7]. of many conditions. The dicarbonyl electrophiles react with A mechanistic link exists between dicarbonyl electrophiles lysine residues and form protein adducts capable of inter- and Alzheimer’s disease development, as dicarbonyl elec- rupting various cellular processes [1, 2]. Elevated levels of trophiles enhance the oligomerization and neurotoxicity of amyloid beta [8, 9]. 2-HOBA can selectively and rapidly scavenge dicarbonyl * Correspondence: [email protected] electrophiles to prevent these dicarbonyl-associated pro- 1MTI BioTech, Inc., Ames, IA 50010, USA 2Department of Kinesiology, Iowa State University, Ames, IA 50010, USA tein modifications [10]. 2-HOBA is naturally occurring Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Pitchford et al. BMC Pharmacology and Toxicology (2020) 21:3 Page 2 of 10 [11] and has been shown to be orally available in rodents Subjects and humans [12, 13]. In mice, 2-HOBA crosses the blood Healthy male and non-pregnant female volunteers be- brain barrier, achieving 2-fold higher 2-HOBA levels in tween the ages of 18 and 59 years were eligible to partici- brain relative to plasma [12]. Critically, 2-HOBA adminis- pate. Subjects were not permitted to take any medications tration protected hApoE4 mice from age-associated work- 2 weeks prior to or during the study. Exclusion criteria in- ing memory deficits [14], suggesting a beneficial effect of cluded known cardiac, kidney, or hepatic disease; presence 2-HOBA-mediated inhibition of dicarbonyl protein modi- of diseases that could manifest morbidity or symptoms/ fication on the maintenance of hippocampal function. signs that could confound interpretation of the study re- In vitro and preclinical safety studies [15–18] did not sults; the need to discontinue any drug administered as indicate any toxicity concerns associated with 2-HOBA standard of care treatment; and the unwillingness or in- acetate within the expected therapeutic dose range. ability to use approved birth-control methods. Similarly, the first-in-human study of 2-HOBA demon- strated excellent safety and tolerability in healthy volun- Multiple dose study design teers at 2-HOBA acetate doses up to 825 mg13. In that This study was a double-blind, randomized, placebo- study, 2-HOBA was rapidly absorbed with maximal controlled, multiple dose escalation study designed to as- plasma concentrations observed 1–2 h after oral admin- sess the safety, tolerability, and pharmacokinetics of istration, and was fully cleared from circulation between multiple-dose 2-HOBA acetate. Nine subjects were stud- 8 and 24 h, suggesting dosing at least every 8 h would be ied per dose level, including 6 receiving 2-HOBA and 3 re- required to maintain acceptable steady-state concentra- ceiving placebo. Randomization was performed by the tions of 2-HOBA. The primary objective of the present study statistician; a computer-generated randomization se- investigation was to evaluate the safety and tolerability quence using the stratified permuted block randomization, of three-times-daily dosing of 2-HOBA. Additional ex- with blocks of size 3, was used to assign participants at the periments were conducted to confirm 2-HOBA does not ratio of 1:2 to placebo or 2-HOBA at each dose level of interfere with cyclooxygenase function and that that or- the treatment. Treatments were provided by the Vander- ally administered 2-HOBA can cross into the cerebro- bilt University Medical Center Pharmacy to study staff; spinal fluid. participants and all study staff were blinded to treatment assignments. The dose levels of 2-HOBA acetate were 500 and 750 mg, which correspond to 336 and 504 mg 2- Methods HOBA, respectively. 2-HOBA acetate was provided in The studies described herein are registered at Clinical- 250-mg capsules; the placebo was identical in appearance Trials.gov (multiple dose study - NCT03555682; cere- and physical properties but contained no 2-HOBA acetate. brospinal fluid penetrance study - NCT03554096). The These doses were designed to achieve peak plasma levels study protocols were approved by the Vanderbilt Uni- at steady state that approximate the peak plasma levels ob- versity Institutional Review Board. All participants pro- served at the two highest doses used in the single dose vided written informed consent before participating. All study [13]. The dose frequency (every 8 h) was also based data was collected at the Vanderbilt University Medical on the single dose pharmacokinetics [13]. Single doses of Center Clinical Research Center between August 2018 2-HOBA acetate given to healthy volunteers resulted in 2- and May 2019. This study and report adhere to CON- HOBA plasma concentrations in the range of 8.5–320 ng/ SORT guidelines. ml at 8 h and no detectable levels 24 h following dose ad- ministration. Thus, an eight-hour dosing interval was se- lected for the multiple dose studies to ensure continued 2- Compound HOBA exposure throughout the dosing interval. 2-HOBA was provided as the acetate salt (CAS 1206675– On Day 1 of the study, volunteers were admitted to 01-5). A commercial production lot produced under GMP the clinical research center following an overnight fast, (#16120312) of 2-HOBA acetate was obtained from TSI and baseline evaluations were performed, including vital (China) Co., Ltd. (Shanghai, China) for use in this study. signs (heart rate, respiration rate, blood pressure, and Our laboratory independently verified the purity of the SpO2), clinical laboratory parameters (blood biochemis- commercial lot to be > 99% via HPLC and NMR spectros- try, hematology, and urinalysis), and 12-lead ECG. The copy. Hard gel capsules (Capsugel, Jiangsu, China) con- first dose of 2-HOBA acetate was administered with taining 250 mg of 2-HOBA acetate (corresponding to 168 water, after which volunteers remained at the CRC for mg 2-HOBA) were prepared by TSI (China) Co., Ltd. Fill 24 h. Breakfast was provided after the baseline measure- weight, weight uniformity, disintegration, 2-HOBA con- ments were performed and the first dose of 2-HOBA tent, acetate content, and microbial and analytical tests was administered. Safety evaluations and potential ad- were within all specification limits. verse event assessments were performed at protocol- Pitchford et al. BMC Pharmacology and Toxicology (2020) 21:3 Page 3 of 10 defined intervals. Volunteers were re-evaluated at the of 2-HOBA during routine analysis of samples demon- clinical research center briefly on day 5 and for 24 h fol- strated an intra-assay precision of 1.1–14.8%, bias − 4.0 lowing the last study dose on day 15. All adverse events – 17.1%, and inter-assay precision of 3.7–9.0%, bias 6.0– were recorded, regardless of whether they were consid- 9.0%. Quantification of salicylic acid in samples was ered to be study-related. Additional follow-up evalua- qualified over the range of 100–5000 ng/mL. In-process tions were conducted by phone on days 3, 4, 8, and 11 analytical performance of salicylic acid during routine of dosing as well as 3 and 7 days after discontinuing 2- analysis of samples demonstrated an intra-assay preci- HOBA acetate.
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