Altered Pharmacokinetics and Metabolism of Valproate after Replacement of Conventional Valproate with the Slow‐Release Formulation in Epileptic Patients

Abstract

Altered metabolism of valproate has been suggested as the mechanism of teratogenicity and hepatotoxicity of valproate. This study aimed at examining whether pharmacokinetics of a slow-release formulation of valproate affects valproate metabolism. Thirty-one epileptic patients were treated with fixed-doses of conventional valproate for at least 2 months. Thereafter, the drug was replaced with the same doses of slow-release formulation of valproate for 2 months. Blood samplings for determination of valproate and its metabolites by gas chromatography-mass spectrometry were performed at three time-points (just before morning dose and at 1 and 5 hr after morning dose) during both treatment phases. There was a significant difference (PϽ0.005) in the mean serum concentration (∫S.D.) of valproate after 1 hr between conventional valproate (63.1∫27.9 mg/ml) and slow-release formulation of valproate (45.7∫19.5 mg/ml). Mean serum concentrations (∫S.D.) of 4-en and hydroxy metabolites after 5 hr were significantly reduced after replacement with slow-release formulation of valproate (4-en: 29.5∫14.0»23.0∫15.3 ng/ml, 3-OH: 488.5∫234.0»419.6∫171.1 ng/ml, 4-OH: 404.3∫124.7»342.8∫147.6 ng/ml, 5-OH: 102.8∫54.4»81.0∫43.6 ng/ml). The present study suggests that smaller diurnal fluctuations in valproate concentrations during treatment with slow-release formulation of valproate result in decreased formations of minor metabolites including 4-en, the most toxic metabolite.

Computerized Tremor Analysis of Valproate‐induced Tremor: A Comparative Study of Controlled‐release versus Conventional Valproate

“…Although we chose a different approach to this topic, our findings are in concordance with previous research (5,10,11). For example, Doughty et al (11) reported data about compliance and satisfaction in epilepsy patients who changed from sodium VPA to a controlled-release formulation.…”

“…The characteristic kinetic profiles of controlled-release VPA as compared with those of conventional VPA were delayed peak time and reduced peak concentration. In addition, Kondo et al (5) showed that the controlled-release VPA formulation causes smaller diurnal fluctuations in serum concentration than does VPA. The smaller fluctuations result in decreased formation of toxic metabolites, which could be of relevance for adverse effects.…”

“…After conventional VPA was in use for ∼40 years, some 10 years ago, a controlled-release formulation of VPA (CR-VPA) was introduced into clinical practice. Generally, it is supposed that CR-VPA, as it decreases peak plasma concentrations, minimizes the occurrence of concentrationdependent side effects (5).…”

What do the suffixes - XR, ER, Chrono, Chronosphere - really mean as it pertains to modified-release antiepileptic drugs?

“…), mechanism for MR, extent of bioavailability (%), requirement for total daily mg dose adjustment for the MR AED vs. the IR formulation, duration of C min maintenance (h), T max (h) for both single dose and steady-state conditions, longest FDA ⁄ European Medicines Agency-approved dosing frequency (h), absorption (52) have been approved for use in the USA for some time; some generic DVPX formulations, both enteric-coated and ER, have recently become available, but these generic formulations are not included in our analysis because of the relative inaccessibility of the pharmacokinetic and formulation data concerning these products. Multiple forms of enteric-coated NaVPA exist worldwide, and several sustained-release (SR) VPA ⁄ NaVPA forms exist worldwide [Japan (53,54); Germany (55)], but only the most broadlyrecognized branded formulations (-Chrono Ò and -Chronosphere Ò ; Sanofi-Aventis, Paris, France) are included here so that the huge class of VPA ⁄ NaVPA formulations available would not dominate the information presented here.…”

Recommendations for the care of women with epilepsy.

“…• There is some evidence that extended-release preparations may be safer in pregancy. 23 • Take total and free levels (if available) of the drug monthly at trough times.…”