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,Emmanuel T Akporiaye,Zefora Alderman,Walter Urba,Brendan Curti

doi:10.1186/s12885-016-2220-6

Abstract

BackgroundAlpha-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.MethodsMale 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.ResultsOur 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.ConclusionWe 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.

Highlights

Alpha-tocopheryloxyacetic acid (α-TEA) is a semi-synthetic derivative of naturally occurring vitamin E that can be delivered via an oral route
Α-TEA has been evaluated as an anti-cancer agent in numerous pre-clinical tumor models [1, 7,8,9,10], efforts to translate these findings into human clinical trials are lacking
After 60 days of tumor monitoring, we found that Alpha-Tocopheryloxyacetic free acid (α-TEA) α-TEA Lysine Salt (LS) significantly inhibit tumor growth (Fig. 2a) and prolonged overall survival compared to control diet (Fig. 2b)

Summary

Introduction

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. Alpha-tocopheryloxyacetic acid (α-TEA) is a semi-synthetic, non-hydrolysable ether derivative of vitamin E. The in vivo anti-tumor activity of α-TEA has been reported in several pre-clinical tumor models [1], and is partially dependent on a T-cell-mediated immune response [3,4,5,6]. Α-TEA has been evaluated as an anti-cancer agent in numerous pre-clinical tumor models [1, 7,8,9,10], efforts to translate these findings into human clinical trials are lacking. FDA) to obtain relevant toxico- and pharmaco-kinetic information in preparation for a first-inhuman trial to evaluate the safety and tolerability of αTEA in patients with advanced cancer. α-TEA lysine salt

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