Lorcaserin for Dravet Syndrome: A Potential Advance Over Fenfluramine?

Progress report on new antiepileptic drugs: A summary of the Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI):II. Drugs in more advanced clinical development

“…Lorcaserin's major circulating and urinary metabolites, the sulfamate (M1) and the N-carbamoyl glucuronide (M5) derivatives, respectively, do not appear to have pharmacological activity. 70,75,77 There was no apparent effect of sex or race on lorcaserin plasma exposure in healthy, overweight, and obese adults. 64,75 In a subgroup of patients from phase 3 trials in obese or overweight adults, body weight was a significant covariate on the apparent clearance and apparent volume of distribution of lorcaserin; patients in the highest body weight quartile had 27% lower mean plasma exposures than patients in the lower body weight quartiles.…”

“…The antiseizure activity of lorcaserin has been shown in several models of seizures 70 . In the GAERS, a well‐established rat model of absence seizures, lorcaserin suppressed seizures in a dose‐dependent manner 68 .…”

“…Lorcaserin is metabolized in the liver by multiple enzymatic pathways, and metabolites are excreted primarily in the urine. Lorcaserin's major circulating and urinary metabolites, the sulfamate (M1) and the N‐carbamoyl glucuronide (M5) derivatives, respectively, do not appear to have pharmacological activity 70,75,77 . There was no apparent effect of sex or race on lorcaserin plasma exposure in healthy, overweight, and obese adults 64,75 .…”

“…No formal analyses have been performed on the effects of other agents on lorcaserin pharmacokinetics. However, as lorcaserin is metabolized by multiple enzymatic pathways involving CYPs as well as sulfotransferases, uridine‐5′‐diphospho‐glucuronosyltransferases (UGTs), and flavin‐containing monooxygenase enzymes, concomitant administration of agents that inhibit drug‐metabolizing enzymes is predicted to have minimal impact on lorcaserin exposure 70,77 …”

“…The antiseizure activity of lorcaserin has been shown in several models of seizures. 70 In the GAERS, a well-established rat model of absence seizures, lorcaserin suppressed seizures in a dose-dependent manner. 68 Antiseizure effects of lorcaserin have also been reported in a zebrafish model of Dravet syndrome, in which stimulation of 5-HT 2C receptors resulted in decreased seizurelike activity.…”