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

Clinical Pharmacokinetics
Patrick E GeorgoffHasan B Alam

Abstract

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. 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. 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...Continue Reading

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Citations

Nov 8, 2018·Expert Opinion on Pharmacotherapy·Alessandra MoranoCarlo Di Bonaventura
Aug 8, 2019·The Journal of Trauma and Acute Care Surgery·Ben E BiesterveldHasan B Alam
Aug 10, 2019·Anesthesia and Analgesia·Ettore CrimiClaudio Napoli
Jan 3, 2019·Shock·Aaron M WilliamsHasan B Alam
Jul 11, 2020·The Journal of Trauma and Acute Care Surgery·Ben E BiesterveldHasan B Alam
Aug 25, 2017·Journal of Neuroscience Research·Bellal JosephPeter Rhee
Apr 14, 2020·The Journal of Trauma and Acute Care Surgery·Rachel RussoHasan B Alam
Jan 19, 2019·International Journal of Molecular Sciences·Andreas von Knethen, Bernhard Brüne
Sep 10, 2020·Frontiers in Pharmacology·Sergi Herve AkoneRolf Müller
Mar 21, 2020·The Journal of Trauma and Acute Care Surgery·Ben E BiesterveldHasan B Alam
Sep 6, 2020·The Journal of Trauma and Acute Care Surgery·Ben E BiesterveldHasan B Alam
Apr 22, 2021·Trauma Surgery & Acute Care Open·Luke PumigliaBen E Biesterveld
May 24, 2021·The Journal of Surgical Research·Ben E BiesterveldHasan B Alam
May 16, 2021·The Journal of Surgical Research·Umar F BhattiHasan B Alam
Jul 30, 2021·Frontiers in Medicine·Renata Brito Falcão-HolandaReinaldo Salomão
Apr 3, 2021·The Journal of Trauma and Acute Care Surgery·Sarah C StokesRachel M Russo

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