Indian Write- Ups

Valproate (VPA) is a major anti-epileptic compound marketed throughout the world and used clinically in a wide variety of patient subgroups.

Sodium valproate is a broad spectrum anti-epileptic and covers a large range of seizure disorders, which include primary generalised seizures and notably, absence and myoclonic seizures where carbamazepine is ineffective. Its use is being recommended in bipolar disorder also, but the pharmacokinetic profile of the usual preparation of valproate is not very favourable due to the following limitations:

• Its elimination half-life is somewhat short, from 8 to 16 h in monotherapy, and markedly reduced when it is associated with enzyme-inducers such as carbamazepine (CBZ), phenytoin (PHT) or phenobarbital (PB).
• It crosses the gastrointestinal barrier too easily. The absorption rate of valproate is very high resulting in a pronounced plasma concentration peak. This peak is followed by a rapid decline in plasma level. For these two reasons, very large fluctuations in plasma levels occur during a 24-h period even with multiple dose administration. These fluctuations are probably not very detrimental to the efficacy of the drug.

VPA is highly protein-bound. Saturation of the protein-binding sites appears at above 80 microgram / ml. Free concentration increases in a non-linear manner with increasing total plasma concentration. Fluctuations in unbound concentrations are generally twice as large as those in total concentration. VPA is restrictively cleared i.e. only the unbound drug can be metabolised. The higher the unbound concentration, greater is the drug clearance. Higher clearance means more of the drug is necessary to achieve useful concentrations. Furthermore, small rises in free drug concentrations could alter pharmacological effects, as more drug can reach the tissues and organs. Some side effects, such as sedation are concentration-dependent and may appear at the time of Cmax or just after it.

There are numerous interactions between VPA and other anti-epileptic drugs. In one group of patients, receiving PHT or CBZ in addition to VPA, any reported side effects were partially avoided by increasing the daily number of doses of all the drugs. Furthermore, the greater the importance of pharmacokinetic interactions, the higher is the risk of changes in metabolic pathways, with an increase in toxic metabolites such as 4-n-VPA and 2,4-n-VPA.

Sustained release formulation

A sustained-release form of VPA(SRVPA) produces more uniform plasma levels. The tablet contains 2/3 sodium valproate and 1/3 valproic acid, the acid being less hygroscopic than the salt. It is made up of very small granules containing both acids and sodium salt. The slow disintegration and dissolution of these tablets, throughout the gastrointestinal tract for 10 to 12 h, ensures a uniform and steady passage into the circulatory stream.

The greater majority of all the patients with epilepsy (94%) can be routinely managed very well with sustained-release VPA. In 97% of the cases, the switch to sustained-release VPA can be made immediately or within a few days without any risk. The seizure-controlling dose remained on an average, the same before and after the changeover. Sustained-release VPA, as the first treatment, also exhibited an excellent benefit-risk ratio. The special "Chrono" sustained release principle of the preparation used here (1 / 3 valproic acid, 2 / 3 sodium valproate, and the matrix), by which peaks in the plasma level of VPA are avoided, additionally resulted in an excellent tolerance; only in 4% of the patients was the tolerance judged to be moderate-to-poor. Side effect rates to the tune of 16% are reported in the literature for treatment with conventional valproates. It was already reported in 1989 that a switch from conventional valproate to a sustained-release formulation leads to a considerable reduction of the side effects.