Combined Immediate-Release and Extended-Release Formulation of Sodium Valproate Provides Stable Plasma Levels for Inhibition of Histone Deacetylation.

Abstract

A modified controlled-release sodium valproate formulation (VAL001, test) was compared with an approved enteric-coated tablet formulation (Absenor, reference). Pharmacokinetics and safety/tolerability were evaluated in healthy subjects to bridge with positive efficacy results from an early-phase patient trial of valproate in combination with chemotherapy in diffuse large B-cell lymphoma. In Part I (n = 12), both formulations were administered as single doses (30 mg/kg) in a randomized crossover fashion. Equivalent exposures (area under the plasma concentration-time curve) for total and free valproate were observed under fasted conditions. Intake with food delayed the absorption of valproate from the test formulation, with no impact on AUC. In Part II (n = 27), both formulations were administered over 3 consecutive days, at 30 mg/kg twice daily (test) or 20 mg/kg 3 times daily (reference). Similar steady-state levels were observed, but fluctuation was less with the test product (23% vs. 47%, P = .0102). Inhibition of histone deacetylase activity was evidenced by increased levels of acetylated H3K9 in peripheral blood mononuclear cells. No serious or severe adverse events were observed. The novel capsule formulation of valproate, containing a combination of immediate-release granules and extended-release pellets, appears to have suitable pharmacokinetic properties for cancer treatments aiming for histone deacetylase inhibition.