Relative bioavailability of different valproic acid formulations

Abstract

Relative bioavailability of valproic acid after oral administration of 2 Convulsofin (test) tablets each containing 300 mg calcium valproate (263.4 mg valproic acid) was studied versus 2 references (2 dragees each of 300 mg calcium valproate, ref.A, 600 mg sodium valproate in liquid form (258.7 mg valproic acid), ref.B). The controlled, randomized, clinical trial was performed in 16 healthy volunteers (12 males, 4 females, body weight 58-100 kg, Broca index 0.85-1.15) according to a 3-period changeover design with 7 days wash-out between 2 periods. Valproic acid was measured in serum with a GC method. Pharmacokinetic evaluation was done by compartment free methods. Test was considered bioequivalent with ref.A or ref.B with reference to extent of absorption if the 90% confidence interval of their AUC ratio was within the range of 0.80-1.25, and with respect to rate of absorption if the 90% confidence intervals of Cmax/AUC ratios were within 0.70-1.43. The point estimators (90% confidence limits) of the AUC ratios of test/ref.A and test/ref.B were 0.952 (0.882-1.028) and 1.063 (0.989-1.141), respectively. The point estimators (90% confidence limits) of Cmax/AUC ratios were 1.005 (0.923-1.094, test/ref.A) and 0.915 (0.845-0.991, test/ref.B). The following Cmax ratios were calculated: 0.957 (0.866-1.057, test/ref.A) and 0.972 (0.886-1.067, test/ref.B). No serious and unexpected adverse events were observed during the clinical trial. Test was bioequivalent with the 2 reference formulations ref.A and ref.B with respect to extent and rate of absorption. However, according to the secondary criterion tmax test tablets were more rapidly bioavailable than ref.A dragees (tmax-difference: -2.6 (-4.8 to -0.3 h) but more slowly (tmax-difference:+0.8 (-1.3 to +2.9 h) than ref.B juice.