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

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.

Conflict of interest statement

Conflicts of interest:

There are no conflicts to declare.

Figures

Figure 1

Screening and enrollment flow chart

Figure 2

Observed mean concentration-time profile of valproic acid (VPA) by dose administration group.

Figure 3. AUCinf and Cmax of weight-based and absolute doses of VPA

Scatter and linear regression fit plot (with equation) of the relationship between area under the concentration-time curve from time zero to infinity (AUCinf) over weight-based dose (A) and absolute dose (B), and the maximum concentration (Cmax) over weight-based dose (C) and absolute dose (D).

Figure 4. Adverse events and VPA dose

Scatter and linear regression fit plot of the number of subject-reported adverse events over VPA dose (mg).