Utilizing an acute hyperthermia-induced seizure test and pharmacokinetic studies to establish optimal dosing regimens in a mouse model of Dravet syndrome

Dravet syndrome often requires polytherapy after monotherapy fails to control seizures, but optimal combination regimens are largely guided by expert opinion rather than data. This study evaluated the efficacy and brain/plasma pharmacokinetics (via Phoenix WinNonlin) of add-on therapies (stiripentol, cannabidiol, lorcaserin, or fenfluramine) combined with clobazam and sodium valproate against hyperthermia-induced seizures in a Scn1a mouse model of Dravet syndrome. Higher doses of stiripentol or cannabidiol added to clobazam and valproate were effective against seizures, with triple-drug combinations producing higher brain concentrations of clobazam and its active metabolite than clobazam monotherapy. The findings support a polypharmacy strategy as a practical preclinical approach for identifying effective drug combinations for Dravet syndrome, with drug-drug interactions likely contributing to the enhanced efficacy observed.