Actual bioavailability of divalproex sodium extended-release tablets and its clinical implications

Divalproex sodium extended-release dosage form (divalproex-ER) has been promoted as innovative formulation for the treatment of epilepsy and manic disorders, and for migraine headache prevention, with the advantage of being dosing once a day. Due to a significant decreasing in the peak-trough fluctuation of plasma valproic acid levels, in comparison with the twice-daily dosing of conventional delayed-release formulations (divalproex-DR), concentration-dependent side effects would be prevented. However the main constraint for divalproex-ER usage is the need to be administered in a higher daily dose, because of its lower bioavailability, in order to prevent eventual breakthrough seizures when patients are switched from the twice-daily divalproex DR regimen. Taking into account free plasma drug levels, divalproex ER/DR relative bioavailability could be assessed as low as 75 percent in fasting condition. In order to overcome the need of increase divalproex-ER daily dose, maintenance of the twice-daily regimen is suggested. Divalproex-ER administered every 12 hours not only increases steady state trough concentration to a higher value in comparison with divalproex-DR, avoiding inefficacy of the treatment, but also achieves the safest manner to treat patients with valproic acid because of reaching practically a plateau profile of drug levels.

Divalproato de sodio de liberación prolongada (divalproex-ER) es un producto innovador que ha sido promovido tanto para el tratamiento de la epilepsia y de los desórdenes maníacos como también para la prevención de la migraña, con la ventaja de poder administrarse una sola vez al día. Dado que la fluctuación de niveles plasmáticos de ácido valproico resulta menor que la originada por la administración dos veces al día del producto convencional de liberación retardada (divalproex-DR), se estarían previniendo los efectos secundarios dependientes de la concentración del fármaco. Sin embargo, y considerando la menor biodisponibilidad del producto, el uso de divalproex-ER tiene el principal inconveniente de necesitar una mayor dosis diaria a los efectos de evitar una eventual reaparición de crisis cuando los pacientes cambian de tratamiento desde divalproex-DR. Teniendo en cuenta los niveles plasmáticos libres del fármaco, la biodisponibilidad relativa divalproex ER/DR podría afirmarse que sea aún más baja, tanto como 75 por ciento cuando los estudios son realizados en ayunas. A los efectos de no incrementar la dosis diaria de divalproex-ER se sugiere mantener un régimen de administración cada 12 horas. La administración de divalproex-ER dos veces al día no sólo incrementa las concentraciones de valle, respecto a divalproex-DR, sino que logra un perfil de niveles de ácido valproico prácticamente de meseta, lográndose así un tratamiento eficaz y con la mayor seguridad para los pacientes.

Effects of Divalproex sodium for Visual Cortex Excitability in Migraine: A Study Using Transcranial Magnetic Stimulation

BACKGROUND: The pathophysiology of migraine has not been fully understood. One of the hypotheses is cortical hyperexcitability. Transcranial magnetic stimulation (TMS) is a noninvasive electrophysiologic tool for the investigation of cortical excitability. Divalproex sodium may prevent migraine attacks by increasing the GABA-ergic tone. We examined the phosphene generation using TMS in migraine patients in order to investigate the cortical excitability and its response by valproate prophylaxis. METHODS: We applied TMS to 27 migraineurs and 27 control subjects. TMS was performed by a Magstim Rapid Stimulator connected to a 70 mm figure-of-eight coil to examine the phosphene threshold between migraineurs and controls on primary (V1) and bilateral secondary (V5) visual cortices. Twelve migraine patients completed a one month administration of divalproex sodium 500 mg/day. We compared the phosphene threshold between pre- and post-treatment with devalproex sodium in these patients. RESULTS: The prevalence of the phosphene generation was significantly higher in migraineurs compared with controls in V1 and V5. The phosphene average thresholds were significantly lower in migraineurs compared with controls in V1 and V5. The phosphene average thresholds in the same areas were significantly higher in post-treatment compared with pre-treatment in migraineurs. CONCLUSIONS: The differences of the phosphene threshold in the visual cortex between migraineurs and controls comply with the theory of cortical hyperexcitability for the pathophysiology of migraine. Valproate might play a significant role in the prophylaxis of migraine by decreasing cortical hyperexcitability.

Effects of the Divalproex Sodium on Cortical Hyperexcitability in Migraine Patients Chung-Ang University,Pildong Hospital

BACKGROUND: Cortical hyperexcitability is proposed to be the putative basis for the physiological disturbances in migraine. Recent studies have demonstrated that divalproex sodium effectively prevents migraine. The cortical silent period (CSP) elicited by transcranial magnetic stimulation (TMS) reflects the cortical inhibition of the central motor pathway. METHODS: We studied the CSP of both first dorsal interossei muscles evoked by TMS in 15 migraine patients and 15 normal subjects. As a prophylactic therapy, 15 migraine patients were treated with divalproex sodium 500~750 mg/day. After 3 months, we studied the CSP in migraine patients for the purpose of comparing with results before medication. RESULTS: The CSP was shorter in migraine patients than in controls (135.8+/-27.8 msec vs 203.7+/-32.2 msec, p<0.001). After treatment with divalproex sodium, the CSP was significantly prolonged in migraine patients (196.9+/-31.0msec, p=0.001). CONCLUSIONS: The shortened CSP in migraine patients suggests increased excitability of the cortical neuron in migraine. The prolonged CSP after medication in migraine patients suggests that the divalproex sodium may play a role in the prophylaxis of migraine by decreasing cortical neuronal hyperexcitability. (J Korean Neurol Assoc 19(5):489~493, 2001)