GMP-grade α-TEA lysine salt: A 28-Day oral toxicity and toxicokinetic study with a 28-Day recovery period in Beagle dogs

Bella S. Guerrouahen, Tobias Hahn, Zefora Alderman, Brendan Curti, Walter Urba, Emmanuel T. Akporiaye

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: Alpha-tocopheryloxyacetic acid (α-TEA) is a semi-synthetic derivative of naturally occurring vitamin E (alpha-tocopherol) that can be delivered via an oral route. Preclinical in vitro and in vivo data demonstrated that α-TEA is a potent anti-tumor agent with a safe toxicity profile in mice. We report a comprehensive study to evaluate the toxokinetics of good manufacturing practice (GMP)-grade α-TEA in dogs after daily oral administration for 28 days, followed by a 28-day recovery period. Methods: Male and female beagle dogs received capsules of α-TEA Lysine Salt at doses of 100, 300, 1500 mg/kg/day. α-TEA plasma levels were determined by high-performance liquid chromatography (HPLC) with mass spectrometric detection. During the treatment, animals were observe for clinical signs, food consumption, body weight, and subjected to ophthalmoscopic, and electrocardiographic assessments. At the end of the dosing period, blood was taken and toxicokinetic analyses and histopathology assessments were performed when animals were necropsied. Results: Our findings showed that there was no α-TEA-related mortality or moribundity. At the highest dose, increases in white blood cells and fibrinogen levels were observed. These levels returned to normal at the end of the recovery period. Histopathological evaluation of major organs revealed no significant lesions related to α-TEA-treatment. Conclusion: We demonstrate that for designing clinical trials in patients, the highest non-severely toxic dose (HNSTD) of α-TEA is 1500 mg/kg/day in Beagle dogs and this data informed the design of dose-escalation studies of α-TEA in patients with advanced cancer.

Original languageEnglish
Article number199
JournalBMC Cancer
Volume16
Issue number1
DOIs
Publication statusPublished - 8 Mar 2016
Externally publishedYes

Fingerprint

Lysine
Salts
Dogs
Poisons
alpha-Tocopherol
Vitamin E
Fibrinogen
Capsules
Oral Administration
Neoplasms
Leukocytes
High Pressure Liquid Chromatography
Body Weight
Clinical Trials
Food
Mortality
Therapeutics
Toxicokinetics
2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid
In Vitro Techniques

Keywords

  • Cancer therapy
  • Non-rodent
  • Pharmacokinetics
  • Toxicokinetic
  • Vitamin analog
  • α-TEA lysine salt

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Cite this

GMP-grade α-TEA lysine salt : A 28-Day oral toxicity and toxicokinetic study with a 28-Day recovery period in Beagle dogs. / Guerrouahen, Bella S.; Hahn, Tobias; Alderman, Zefora; Curti, Brendan; Urba, Walter; Akporiaye, Emmanuel T.

In: BMC Cancer, Vol. 16, No. 1, 199, 08.03.2016.

Research output: Contribution to journalArticle

Guerrouahen, Bella S. ; Hahn, Tobias ; Alderman, Zefora ; Curti, Brendan ; Urba, Walter ; Akporiaye, Emmanuel T. / GMP-grade α-TEA lysine salt : A 28-Day oral toxicity and toxicokinetic study with a 28-Day recovery period in Beagle dogs. In: BMC Cancer. 2016 ; Vol. 16, No. 1.
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AU - Akporiaye, Emmanuel T.

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AB - Background: Alpha-tocopheryloxyacetic acid (α-TEA) is a semi-synthetic derivative of naturally occurring vitamin E (alpha-tocopherol) that can be delivered via an oral route. Preclinical in vitro and in vivo data demonstrated that α-TEA is a potent anti-tumor agent with a safe toxicity profile in mice. We report a comprehensive study to evaluate the toxokinetics of good manufacturing practice (GMP)-grade α-TEA in dogs after daily oral administration for 28 days, followed by a 28-day recovery period. Methods: Male and female beagle dogs received capsules of α-TEA Lysine Salt at doses of 100, 300, 1500 mg/kg/day. α-TEA plasma levels were determined by high-performance liquid chromatography (HPLC) with mass spectrometric detection. During the treatment, animals were observe for clinical signs, food consumption, body weight, and subjected to ophthalmoscopic, and electrocardiographic assessments. At the end of the dosing period, blood was taken and toxicokinetic analyses and histopathology assessments were performed when animals were necropsied. Results: Our findings showed that there was no α-TEA-related mortality or moribundity. At the highest dose, increases in white blood cells and fibrinogen levels were observed. These levels returned to normal at the end of the recovery period. Histopathological evaluation of major organs revealed no significant lesions related to α-TEA-treatment. Conclusion: We demonstrate that for designing clinical trials in patients, the highest non-severely toxic dose (HNSTD) of α-TEA is 1500 mg/kg/day in Beagle dogs and this data informed the design of dose-escalation studies of α-TEA in patients with advanced cancer.

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