This article reviews relevant pharmacologic and clinical information gathered for
valproate since it was introduced into clinical practice 37 years ago and the application of this information for the treatment of childhood
epilepsy.
Valproate is available for oral and parenteral use. Oral forms are almost completely bioavailable but the rate of absorption varies between formulations. The Chrono
tablet formulation has not been adapted for children aged <6 years, in whom the oral
solution or syrup, requiring two or three daily administrations, has been used until recently. A new formulation specifically adapted for children, Chronosphere, administrated once or twice daily, is a modified-release formulation of
valproate that minimizes fluctuations in serum
drug concentrations during a dosage interval.
Plasma protein binding is 80-94% and tends to decrease with increasing
drug concentration.
Valproate elimination is markedly decreased in newborns compared with older children and adults. Elimination by glucuronidation only becomes fully effective by the age of 3-4 years. In children aged 2-10 years receiving
valproate, plasma clearances are 50% higher than those in adults. Over the age of 10 years, pharmacokinetic parameters approximate those of adults.
Valproate can increase plasma concentrations of concomitant drugs, such as
phenobarbital and
lamotrigine, by inhibiting their metabolism. As a result of its broad spectrum of efficacy in a wide range of seizure types and
epilepsy syndromes,
valproate is a
drug of choice for children with newly diagnosed
epilepsy (focal or generalized),
idiopathic generalized epilepsy,
epilepsies with prominent
myoclonic seizures or with multiple seizure types, and
photosensitive epilepsies. In the group of cognitive
epilepsies, in which severe spike and wave discharges are accompanied by cognitive deterioration,
valproate,
ethosuximide, or both should be tested before using
corticosteroids. In comparative trials with
carbamazepine,
phenytoin, and
phenobarbital in
focal epilepsy and with
ethosuximide in
absence epilepsy,
valproate was as effective and showed a favorable tolerability profile, with minimal adverse cognitive and CNS effects. The low potential for paradoxical seizure aggravation and the long-term efficacy of the
drug are additional important factors that contribute to its excellent profile. Intravenous
valproate may be effective for the treatment of convulsive and
non-convulsive status epilepticus that is refractory to conventional drugs. In infants, potential benefits should be carefully weighed against the risk of liver toxicity. Gastrointestinal intolerance is a relatively frequent, dose-related adverse effect of the
drug in children. Bodyweight increase and
tremor may be observed in older children and adolescents. Despite the challenge of newer drugs,
valproate remains a gold standard
antiepileptic drug for the treatment of children.