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

• Published in: Clinical pharmacokinetics Vol. 57; no. 2; pp. 209 - 219
• Main Authors: Georgoff, Patrick E., Nikolian, Vahagn C., Bonham, Tess, Pai, Manjunath P., Tafatia, Celia, Halaweish, Ihab, To, Kathleen, Watcharotone, Kuanwong, Parameswaran, Aishwarya, Luo, Ruijuan, Sun, Duxin, Alam, Hasan B.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2018; Springer Nature B.V
• Subjects: Acids; Administration, Intravenous; Adolescent; Adult; Alcohol; Blood & organ donations; Cancer; Chromatin; Dose-Response Relationship, Drug; Double-Blind Method; Drug dosages; Family medical history; FDA approval; Female; Gene expression; Hemorrhage; Hemorrhagic shock; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - adverse effects; Humans; Internal Medicine; Kinases; Male; Maximum Tolerated Dose; Medicine; Medicine & Public Health; Middle Aged; Models, Biological; Mortality; NCT; NCT01951560; Original Research Article; Pharmacology/Toxicology; Pharmacotherapy; Prescription drugs; Sepsis; Studies; Substance abuse treatment; Trauma; Traumatic brain injury; Valproic Acid - administration & dosage; Valproic Acid - adverse effects; Young Adult; United States > US
• ISSN: 0312-5963; 1179-1926; 1179-1926
• DOI: 10.1007/s40262-017-0553-1

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