title: GMP-grade α-TEA lysine salt: a 28-Day oral toxicity and toxicokinetic study with a 28-Day recovery period in Beagle dogs.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Sidra Medical and Research Center, Experimental Biology Division - Research, PO Box 26999, Doha, Qatar. bguerrouahen@sidra.org.
authors.forename: Bella S
authors.initials: BS
authors.lastname: Guerrouahen
authors.affiliation: Laboratory of Tumor Immunology and Therapeutics, Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. 2N35, Portland, OR, USA. thahn.co@icloud.com.
authors.forename: Tobias
authors.initials: T
authors.lastname: Hahn
authors.affiliation: Laboratory of Tumor Immunology and Therapeutics, Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. 2N35, Portland, OR, USA. zefalder@gmail.com.
authors.forename: Zefora
authors.initials: Z
authors.lastname: Alderman
authors.affiliation: Laboratory of Tumor Immunology and Therapeutics, Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. 2N35, Portland, OR, USA. Brendan.Curti@providence.org.
authors.forename: Brendan
authors.initials: B
authors.lastname: Curti
authors.affiliation: Laboratory of Tumor Immunology and Therapeutics, Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. 2N35, Portland, OR, USA. Walter.Urba@providence.org.
authors.forename: Walter
authors.initials: W
authors.lastname: Urba
authors.affiliation: Sidra Medical and Research Center, Experimental Biology Division - Research, PO Box 26999, Doha, Qatar. eakporiaye@sidra.org.|Laboratory of Tumor Immunology and Therapeutics, Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. 2N35, Portland, OR, USA. eakporiaye@sidra.org.
authors.forename: Emmanuel T
authors.initials: ET
authors.lastname: Akporiaye
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D001706:Biopsy; D001772:Blood Cell Count; D001774:Blood Chemical Analysis; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D004285:Dogs; D005260:Female; D008239:Lysine; D008297:Male; D012492:Salts; D013997:Time Factors; D024505:Tocopherols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D018675:Toxicity Tests; D066007:Toxicokinetics; D016482:Urinalysis
chemical_list: D000970:Antineoplastic Agents; D012492:Salts; C488288:2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid; D008239:Lysine; D024505:Tocopherols