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Safety and Tolerability of Intravenous Valproic Acid in Healthy Subjects: A Phase I Dose-Escalation Trial

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Abstract

Background

Valproic acid, a histone deacetylase inhibitor, has beneficial effects in the setting of cancer, neurologic diseases, and traumatic injuries. In animal models of traumatic injury, a single dose of valproic acid has been shown to reduce mortality. The purpose of this trial was to determine the maximum tolerated single dose of intravenous valproic acid in healthy humans.

Methods

A double-blinded, placebo-controlled, dose-escalation trial design was used to identify dose-limiting toxicities in healthy subjects who received a single dose of intravenous valproic acid. Patients were monitored for adverse events and data were collected for pharmacokinetic, pharmacodynamic, and safety profiling of valproic acid.

Results

Fifty-nine healthy subjects (mean 30 ± 12 years) were enrolled. Forty-four subjects received valproic acid in doses from 15 to 150 mg/kg. The most common adverse events were hypoacusis (n = 19), chills (n = 18), and headache (n = 16). The maximum tolerated dose was 140 mg/kg. Dose-limiting toxicities included headache and nausea lasting longer than 12 h. No drug-related abnormalities were seen in other safety measures including laboratory tests, hemodynamic parameters, cardiac rhythm monitoring, and cognitive testing. A two-compartment model was predictive of valproic acid concentration–time profiles, with a strong correlation (R 2 = 0.56) observed between the number of reported adverse events and the dose level.

Conclusions

The maximum tolerated dose of intravenous valproic acid in healthy subjects is 140 mg/kg. This is significantly higher than the previously established maximum tolerated dose of 60–75 mg/kg. Next, the safety and tolerability of high-dose valproic acid will be tested in trauma patients in hemorrhagic shock.

ClinicalTrials.gov Identifier: NCT01951560

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Author notes

  1. Patrick E. Georgoff and Vahagn C. Nikolian contributed equally to the article.

Authors and Affiliations

  1. Department of General Surgery, University of Michigan Medical School, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA

    Patrick E. Georgoff, Vahagn C. Nikolian, Tess Bonham, Celia Tafatia, Ihab Halaweish, Kathleen To & Hasan B. Alam

  2. Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA

    Manjunath P. Pai

  3. Michigan Institute for Clinical and Health Research, University of Michigan Medical School, Ann Arbor, MI, USA

    Kuanwong Watcharotone & Aishwarya Parameswaran

  4. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA

    Ruijuan Luo & Duxin Sun

Authors
  1. Patrick E. Georgoff
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  2. Vahagn C. Nikolian
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  12. Hasan B. Alam
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Corresponding author

Correspondence to Hasan B. Alam.

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Funding

This work was funded by the Department of Defense Office of Naval Research (N000141310071) and the National Institutes of Health Center for Advancing Translational Sciences (UL1TR000433). The Michigan Institute for Clinical Health Research provided guidance, data design, and clinical research space. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, or the US Department of Defense.

Conflict of interest

Patrick E. Geogoff, Vahagn C. Nikolian, Tess Bonham, Manjunath P. Pai, Celia Tafatia, Ihab Halaweish, Kathleen To, Kuanwong Watcharotone, Aishwarya Parameswaran, Ruijuan Lao, Duxin Sun, and Hasan B. Alam have no conflicts of interest directly relevant to the contents of this study.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Georgoff, P.E., Nikolian, V.C., Bonham, T. et al. Safety and Tolerability of Intravenous Valproic Acid in Healthy Subjects: A Phase I Dose-Escalation Trial. Clin Pharmacokinet 57, 209–219 (2018). https://doi.org/10.1007/s40262-017-0553-1

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