RELATIVE BIOAVAILABILITY OF DIFFERENT VALPROIC ACID FORMULATIONS

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 e ach of 300 mg calcium valproate, ref.A, 600 mg sodium valproate in liq uid form (258.7 mg valproic acid), ref.B). The controlled, randomized, clinical trial was performed in 16 healthy volunteers (12 males, 4 fe males, 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. Valpr oic acid was measured in serum with a GC method. Pharmacokinetic evalu ation was done by compartment free methods. Test was considered bioequ ivalent 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% confiden ce intervals of C-max/AUC ratios were within 0.70-1.43. The point esti mators (90% confidence limits) Of the AVC ratios of test/ref.A and tes t/ref.B were 0.952 (0.882-1.028) and 1.063 (0.989-1.141), respectively . The point estimators (90% confidence limits) of C-max/AUC ratios wer e 1.005 (0.923-1.094, test/ref.A) and 0.915 (0.845-0.991, test/ref.B). The following C-max 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 bioeq uivalent with the 2 reference formulations ref.A and ref.B with respec t to extent and rate of absorption. However, according to the secondar y criterion t(max) test tablets were more rapidly bioavailable than re f.A dragees (t(max)-difference: -2.6 (-4.8 to -0.3 h) but more slowly (t(max)-difference: +0.8 (-1.3 to +2.9 h) than ref.B juice.