Vitamin E delta-tocotrienol (VEDT) has demonstrated chemopreventive and antineoplastic activity in preclinical models. The aim of our study was to determine the safety and pharmacokinetics of VEDT and its metabolites after single- and multiple-dose administrations in healthy subjects.
Thirty-six subjects received from 100 to 1600 mg of oral VEDT as a single dose or twice daily for 14 consecutive days. A 3 + 3 dose escalation design was utilized. Pharmacokinetic data were derived from high-performance liquid chromatography (HPLC) assays. Serial blood and urine samples were collected before and during VEDT administration, with serum and urine metabolites assessed using HPLC.
No drug-related adverse events were observed. Pharmacokinetic parameters for single and multiple doses were, respectively, as follows (shown as range): time to maximum concentration of 4–9.3 and 4.7–7.3 h, maximum concentration of 795.6–3742.6 and 493.3–3746 ng/mL, half-life of 1.7–5.9 and 2.3–6.9 h, and 0–12 h area under the curve of 4518.7–20,781.4 and 1987.7–22,171.2 ng h/mL. Plasma tocotrienols were significantly increased after VEDT administration, indicating oral bioavailability of VEDT in humans. Plasma and urine levels of metabolites, δ-carboxyethyl hydroxychroman, and δ-carboxymethylbutyl hydroxychroman were elevated after VEDT administration in a dose-dependent manner and were 30–60 times significantly higher than δ-tocotrienol levels. VEDT can be safely administered at doses up to 1600 mg twice daily. Plasma VEDT concentrations were comparable to those obtained in VEDT-treated mice in which tumor growth was delayed.
Our results suggest that VEDT can be safely consumed by healthy subjects and achieve bioactive levels, supporting the investigation of VEDT for chemoprevention.
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We thank Rasa Hamilton (Moffitt Cancer Center) for editorial assistance.
The study was supported in part by National Cancer Institute Grant 1RO1 CA-129227-01A1. Our study also received valuable assistance from the Clinical Pharmacology Lab of the Translational Research Core Facility at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center (P30-CA076292).
Conflict of interest
Dr. Malafa is named as an inventor on the US Patent “Delta-Tocotrienol Treatment and Prevention of Pancreatic Cancer” (June 26, 2007; OTML docket number 06A069), but does not have financial interest in the companies that have licensed this patent. All other authors have no conflicts of interest to disclose.
Research involving human participants and/or animals and Informed consent
All participants provided written inform consent, and the study was conducted in accordance with the applicable guidelines on Good Clinical Practice.
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Mahipal, A., Klapman, J., Vignesh, S. et al. Pharmacokinetics and safety of vitamin E δ-tocotrienol after single and multiple doses in healthy subjects with measurement of vitamin E metabolites. Cancer Chemother Pharmacol 78, 157–165 (2016). https://doi.org/10.1007/s00280-016-3048-0