Stiripentol

STIRIPENTOL

Stiripentol, though not a new molecule, was approved in Europe in 2007 for a very specific type of epilepsy. The drug is used with clobazam and valproate in the adjunctive therapy of refractory generalized tonic-clonic seizures in patients with severe myoclo-nic epilepsy of infancy (SMEI, Dravet’s syndrome) whose sei-zures are not adequately controlled with clobazam and valproate. The drug is legally imported into the USA on a compassionate use basis. The mechanism of action of stiripentol is not well understood but it has been shown to enhance GABAergic trans-mission in the brain, partly through a barbiturate-like effect, ie, prolonged opening of the Cl^– channels in GABA_A receptors. It also increases GABA levels in the brain. It can increase the effect of other AEDs by slowing their inactivation by cytochrome P450.Stiripentol is a potent inhibitor of CYP3A4, CYP1A2, and CYP2C19. Adverse effects of stiripentol itself are few, but the drug can dramatically increase the levels of valproate, clobazam, and the active metabolite of the latter, norclobazam. These drugs must be used cautiously together to avoid adverse effects. Dosing is com-plex, typically beginning with a reduction of the concomitant medication; stiripentol is then started at 10 mg/kg/d and increased gradually to tolerability or to much higher doses. The kinetics of stiripentol are nonlinear.