Dose optimization of early high-dose valproic acid for neuroprotection in a swine cardiac arrest model

AIM: High-dose valproic acid (VPA) improves the survival and neurologic outcomes after asphyxial cardiac arrest (CA) in rats. We characterized the pharmacokinetics, pharmacodynamics, and safety of high-dose VPA in a swine CA model to advance clinical translation. METHODS: After 8 ​min of untreated ventricular fibrillation CA, 20 male Yorkshire swine were resuscitated until return of spontaneous circulation (ROSC). They were block randomized to receive placebo, 75 ​mg/kg, 150 ​mg/kg, or 300 ​mg/kg VPA as 90-min intravenous infusion (n ​= ​5/group) beginning at ROSC. Animals were monitored for 2 additional hours then euthanized. Experimental operators were blinded to treatments. RESULTS: The mean(SD) total CA duration was 14.8(1.2) minutes. 300 ​mg/kg VPA animals required more adrenaline to maintain mean arterial pressure ≥80 ​mmHg and had worse lactic acidosis. There was a strong linear correlation between plasma free VPA C(max) and brain total VPA (r(2) ​= ​0.9494; p ​< ​0.0001). VPA induced dose-dependent increases in pan- and site-specific histone H3 and H4 acetylation in the brain. Plasma free VPA C(max) is a better predictor than peripheral blood mononuclear cell histone acetylation for brain H3 and H4 acetylation (r(2) ​= ​0.7189 for H3K27ac, r(2) ​= ​0.7189 for pan-H3ac, and r(2) ​= ​0.7554 for pan-H4ac; p ​< ​0.0001). CONCLUSIONS: Up to 150 ​mg/kg VPA can be safely tolerated as 90-min intravenous infusion in a swine CA model. High-dose VPA induced dose-dependent increases in brain histone H3 and H4 acetylation, which can be predicted by plasma free VPA C(max) as the pharmacodynamics biomarker for VPA target engagement after CA.