Pharmacokinetic characteristics of a new multiple unit sustained release formulation of sodium valproate

Abstract

Aim: Two bioavailability studies were conducted in healthy male volunteers to determine the absorption characteristics of a new dosage form of sodium valproate consisting of sustained release pellets in a hard gelatine capsule.

Subjects, material and methods: To obtain first data on the in vivo behavior of the new multiple unit formulation a single dose pilot study in comparison with an oral solution was performed in 6 volunteers. Following the pilot study the pharmacokinetics were investigated versus a conventional enteric-coated tablet after multiple dosing in 18 volunteers. The volunteers were administered either a single or multiple dose of 300 mg sodium valproate. In both studies a wash-out period of at least 1 week elapsed between the periods. Valproic acid was determined from serum by gas chromatography at intervals suitable for obtaining concentration time curves for both regimens.

Results: The results of the pilot study showed that the valproate concentration in serum following administration of the new sustained release capsule increased smoothly and a longer lasting plateau was observed as compared with the solution. The average maximum serum valproate concentration of 12.5 microg/ml (sustained release capsule) and 24.3 microg/ml (solution) appeared at 9.3 h and 0.58 h after dosing. The extent of valproate absorption as reflected in the AUC data for each formulation was equivalent for the new sustained release capsule and reference formulation (AUC0-infinity: 369 +/- 88.9 and 339 +/- 76.2 microg/ml x h). Data obtained after multiple dose administration provided an indication of the consistency of valproate absorption from each dosage form. The time concentration profiles following twice daily administration of 300 mg sodium valproate in the multiple dose study showed that the extent parameters for absorption of valproate (AUC(8tau9tau) = 842 +/- 166 microg/ml x h) are equivalent with the enteric-coated preparation (AUC(8tau9tau) = 823 +/- 139 microg/ml x h). However, the fluctuation of the new sustained release formulation (PTF(8tau9tau) = 0.33 +/- 0.09) is about only one third of the fluctuation observed with the enteric-coated formulation (PTF(8tau9tau) = 0.88 +/- 0.22) when administered twice daily.

Conclusion: These data indicate that the new sustained release capsule possesses desirable absorption characteristics in a form that allows twice daily or even once daily dosing and therefore improves patient compliance.