Stiripentol: an example of antiepileptic drug development in childhood epilepsies.
The efficacy of stiripentol (STP) in Dravet Syndrome (DS) was discovered first in an exploratory study in pediatric pharmacoresistant epilepsies. This efficacy signal, used as a proof of concept, led to - two independent multicenter randomized, double-blind, placebo-controlled trials in DS patients: STICLO-France and STICLO-Italy. In adjunction to valproate and clobazam, STP demonstrated marked efficacy and these trials became the basis for the registration of STP as an orphan drug for DS. Although STP had previously shown antiepileptic activity, since it inhibits cytochromes P450, the increased plasma levels of clobazam (CLB), norclobazam (NCLB), and NCLB/CLB ratio reported in STICLO studies brought into question the activity of STP per se. Recent pharmacological studies demonstrated that (i) STP is a direct allosteric modulator of the GABA receptors at a site distinct from benzodiazepines; (ii) STP and CLB/NCLB act independently at GABA(A) receptors; (iii) their combination increases the maximum response beyond that of either drug alone. All these effects are independent of considerations of changes in metabolism. Some responders in STICLO studies failed to display any increase of plasmatic concentrations of NCLB/CLB ratio as STP could not inhibit CYP2C19 because of its inhibition by progabide or due to an inactivating CYP polymorphism. The responder rate proved to be in the same range whether the NCLB/CLB ratio increased or not. These analyses confirmed that the effects of STP cannot result from a simple pharmacokinetic interaction. We propose that the success of STP should serve as a model for AED development in rare pediatric epileptic syndromes.
Department of Pediatric Neurology, Centre de Reference des Epilepsies Rares, Inserm U663, Hopital Necker Enfants Malades, APHP, Paris Descartes University, Paris, France. rimanabbout@yahoo.com
Rima
R
Nabbout
Catherine
C
Chiron
D000927:Anticonvulsants / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000627:therapeutic use; D002648:Child; D000078306:Clobazam; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004148:Dioxolanes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004827:Epilepsy / Q000188:drug therapy*; D006801:Humans; D016032:Randomized Controlled Trials as Topic
D000927:Anticonvulsants; D004148:Dioxolanes; D001569:Benzodiazepines; D000078306:Clobazam; D003577:Cytochrome P-450 Enzyme System; C021092:stiripentol