OBJECTIVE: To assess efficacy and tolerability of stiripentol (STP) as adjunctive treatment in Dravet syndrome and non-Dravet refractory developmental and epileptic encephalopathies (DREEs).
METHODS: Retrospective observational study of all children and adults with DREE and prescribed adjunctive STP at Hospital Ruber Internacional from January 2000 to February 2023. Outcomes were retention rate, responder rate (proportion of patients with ≥50% reduction in total seizure frequency relative to baseline), seizure freedom rate, responder rate for status epilepticus, rate of adverse event and individual adverse events, reported at 3, 6, and 12 months and at final visit. Seizure outcomes are reported overall, and for Dravet and non-Dravet subgroups.
RESULTS: A total of 82 patients (55 Dravet syndrome and 27 non-Dravet DREE) were included. Median age was 5 years (range 1-59 years), and median age of epilepsy onset was younger in the Dravet group (4.9 [3.6-6] months) than non-Dravet (17.9 [6-42.3], P < 0.001). Median follow-up time STP was 24.1 months (2 years; range 0.3-164 months) and was longer in the Dravet group (35.9 months; range 0.8-164) than non-Dravet (17 months range 0.3-62.3, P < 0.001). At 12 months, retention rate, responder rate and seizure free rate was 68.3% (56/82), 65% [48-77%] and 18% [5.7-29%], respectively. There were no statistically significant differences between groups on these seizure outcomes. Adverse events were reported in 46.3% of patients (38/82), without differences between groups.
CONCLUSIONS: In this population of patients with epileptic and developmental encephalopathies, outcomes with adjunctive STP were similar in patients with non-Dravet DREE to patients with Dravet syndrome.

New-generation antiepileptic drugs as perampanel, rufinamide and stiripentol emerged as alternatives in chronic epilepsy polytherapy. Hence, their metabolic stability and potential involvement in relevant drug-drug interactions (DDI) are of great clinical interest, being HepaRG cells herein used as an in vitro human model. To characterize their metabolic stability profiles, HepaRG cells were incubated with perampanel (1 μM), rufinamide (100 μM) or stiripentol (5 μM) for 12-h. HepaRG cells, pretreated with known CYP450 isoenzymes inducers (rifampicin, phenytoin, phenobarbital, omeprazole and carbamazepine), were also incubated with perampanel, rufinamide or stiripentol to assess possible DDI mediated by CYP450 induction. Results suggest a considerable decrease in perampanel and stiripentol concentrations over 12-h; contrary, rufinamide concentrations did not variated. Cells pretreatment with all inducers significantly decreased stiripentol concentrations (between 20.3% and 31.9%), suggesting a considerable potential for DDI. Rufinamide concentrations only decreased when preincubated with rifampicin and with the highest tested concentrations of the remaining inducers. Perampanel levels decreased with rifampicin, carbamazepine and phenobarbital, supporting the involvement of CYP3A4-mediated metabolism. Besides relevant information concerning the metabolic stability profile and potential DDIs of the new antiepileptics here studied, it was also reinforced the HepaRG cells suitability as a reliable in vitro model to foresee in vivo metabolism in humans.

A post-marketing surveillance study is investigating the safety and effectiveness of stiripentol during real-world clinical use in Japanese patients with Dravet syndrome (DS).
The safety and effectiveness of stiripentol were prospectively investigated over 104 weeks in all patients with DS who were administered the drug from November 2012 through July 2019 in Japan. Patients administered stiripentol for the first time after its approval were defined as \"new patients,\" and those who continued to take the drug after participating in domestic clinical studies were defined as \"continuous-use patients.\" The responder rate was defined as the proportion of patients with a ≥50 % decrease in seizure episodes at the time of assessment of stiripentol effectiveness compared with the 4 weeks before starting stiripentol. Overall improvement was evaluated by the physician in charge based on the comprehensive assessment of the patient\'s condition after stiripentol treatment.
Of 411 patients whose information was collected, 410 patients (376 new and 34 continuous-use) were included in the safety analysis set, and 409 (376 new and 33 continuous-use) were included in the effectiveness analysis set. The median age of new patients was 7 years (range: 0.5-50 years) at the time of stiripentol initiation; 99 % of patients were taking concomitant sodium valproate and 93 % clobazam. Adverse drug reactions occurred in 70 % of new patients; the most common were somnolence (39 %) and loss of appetite (25 %). No new safety concerns due to stiripentol were observed. The responder rate in new patients was 43 % (110/257 patients) for convulsive seizures (tonic-clonic and/or clonic convulsions), 55 % (58/105 patients) for focal impaired awareness seizures, and 62 % (56/90 patients) for generalized myoclonic seizures and/or generalized atypical absence seizures. Overall improvement (after 104 weeks or at the time of drug discontinuation) was rated as marked or moderate in 160/353 of new patients (45 %).
Stiripentol is safe and effective during long-term use in patients with DS in routine clinical practice.

To assess the long-term efficacy and tolerability of stiripentol (STP) as an adjunctive treatment in different forms of refractory epilepsies.
The medical records of all individuals consecutively treated with STP as add-on therapy for refractory epilepsies, irrespective of their being focal, generalized, or both, and followed at Meyer Children\'s Hospital between January 2007 and May 2018, were reviewed. The drug scheme administration consisted of a starting dose of STP of 10-15 mg/kg/d with increments every week, up to a maximum of 50 mg/kg/d, based on both age and weight. Etiology of epilepsy was codified as structural, genetic, infectious, immune, metabolic, and unknown. Responders were defined as patients who achieved a seizure frequency reduction of ≥50%. Retention rate was defined as the probability of continuing STP without additional therapy. Tolerability was assessed by reporting adverse events.
A total of 132 individuals aged from 5 months to 43 years received add-on STP, including 30 patients with Dravet syndrome (DS). The median follow-up was 14.8 months (range = 4 months-18 years, interquartile range = 25.72). Twenty-nine individuals (22%) received more than two antiepileptic drugs. Benzodiazepines, mainly clobazam, were the most commonly used add-on drugs. Sixty-six patients (50%) were responders, and 13 of them (9.8%) were seizure-free. Responder rate was higher in the genetic etiology group (57%), especially in DS (18/30; 60%), and in patients with refractory focal onset epilepsy without bilateral tonic-clonic seizures (5/15; 33%). The median relapse-free survival was 27 months in the 66 responders. The median time to STP failure was 24.6 months in all 132 individuals.
This study confirms the long-term efficacy of add-on STP treatment in patients with different types of refractory epilepsies, including focal onset epilepsy without bilateral tonic-clonic seizures. Further confirmations based on prospectively designed studies are required to confirm STP efficacy in focal epilepsy.

GW Pharmaceuticals\' formulation of highly purified cannabidiol oral solution is approved in the United States for seizures associated with Lennox-Gastaut and Dravet syndromes in patients aged ≥2 years, for which clobazam, stiripentol, and valproate are commonly used antiepileptic drugs. This open-label, fixed-sequence, drug-drug interaction, healthy volunteer trial investigated the impact of cannabidiol on steady-state pharmacokinetics of clobazam (and N-desmethylclobazam), stiripentol, and valproate; the reciprocal effect of clobazam, stiripentol, and valproate on cannabidiol and its major metabolites (7-hydroxy-cannabidiol [7-OH-CBD] and 7-carboxy-cannabidiol [7-COOH-CBD]); and cannabidiol safety and tolerability when coadministered with each antiepileptic drug. Concomitant cannabidiol had little effect on clobazam exposure (maximum concentration [Cmax ] and area under the concentration-time curve [AUC], 1.2-fold), N-desmethylclobazam exposure increased (Cmax and AUC, 3.4-fold), stiripentol exposure increased slightly (Cmax , 1.3-fold; AUC, 1.6-fold), while no clinically relevant effect on valproate exposure was observed. Concomitant clobazam with cannabidiol increased 7-OH-CBD exposure (Cmax , 1.7-fold; AUC, 1.5-fold), without notable 7-COOH-CBD or cannabidiol increases. Stiripentol decreased 7-OH-CBD exposure by 29% and 7-COOH-CBD exposure by 13%. There was no effect of valproate on cannabidiol or its metabolites. Cannabidiol was moderately well tolerated, with similar incidences of adverse events reported when coadministered with clobazam, stiripentol, or valproate. There were no deaths, serious adverse events, pregnancies, or other clinically significant safety findings.

The aim of this study was to assess outcome and seizure response to treatment with stiripentol (STP) associated to valproate (VPA) and clobazam (CLB), which we have used in our center since the 1990s, in patients with Dravet syndrome (DS).
We performed a cross-sectional study of all DS patients with SCN1A mutations who had at least one visit to our center in 2013. A total of 54 patients were included (32 males, 22 females), whose ages ranged from 2.5 to 22 years.
Seizure onset ranged from 2 to 9 months (mean 5 months). Treatment started at a mean age of 7 months with valproate (VPA) as first therapy in 83% of patients. STP was prescribed in 96% at an average age of 20 months. At last follow-up (up to 22 years, median 8 years), 96% were still receiving STP, with VPA and clobazam (CLB) in 91%. Additional therapies were prescribed in 72% of patients. Most patients (96%) continued to have clonic or tonic-clonic seizures but they were brief (<5min, with last status epilepticus (SE) episode being before 4 years of age). Seizures occurred weekly (>3/month) in 38% of patients, monthly (1-3/month) in 40%, and yearly in the remaining patients. None presented with daily seizures. Seizure frequency at last visit was related to the age of treatment initiation, the age of last SE, and SCN1A mutation type.
Triple therapy with STP, VPA, and CLB was maintained long-term by 96% of this large DS cohort because the reduced frequency and severity of seizures STP provided when added to CLB and VPA was durable. Nevertheless, only a few patients achieved seizure freedom and persisting seizures remains a concern in the majority of patients.

BACKGROUND: We have previously shown the benefits of short-term add-on stiripentol therapy for Dravet syndrome inadequately controlled by clobazam and valproate in Japanese patients. We report here the outcomes of long-term stiripentol use.
METHODS: Patients with Dravet syndrome having ≥4 clonic/tonic-clonic seizures per 30 days while on clobazam and valproate (with or without bromide) received add-on stiripentol for 16 weeks. Those benefiting from stiripentol (50mg/kg/day; up to 2500mg/day) continued the therapy for additional up to 40 weeks. Responders were defined as those whose clonic/tonic-clonic seizures became ≤50% frequent as compared to baseline.
RESULTS: Of 24 patients starting stiripentol, 21 received the drug for >16 weeks and 19 completed the study. At the endpoint, the responder rate was 54%, with 2 patients remaining clonic/tonic-clonic seizure-free. Twenty-two patients experienced stiripentol-related adverse events, with two having severe ones. They included somnolence (79%), loss of appetite (67%), ataxia (58%), and elevated gamma-glutamyltransferase (38%). No adverse events led to study discontinuation, but 19 patients required dose reduction for stiripentol and/or either antiepileptic drug combined. Stiripentol dose reduction was done in 9 patients, mostly due to somnolence or loss of appetite.
CONCLUSIONS: During adjunctive stiripentol use with clobazam and valproate, careful monitoring for adverse events such as somnolence and loss of appetite is recommended, and dose reduction may become needed for any of the antiepileptics. Despite the need for safety precautions, the durable responses to stiripentol for up to 56 weeks suggest that the drug is effective as an adjunct to clobazam and valproate for the treatment of Dravet syndrome.

OBJECTIVE: To review the efficacy and tolerability of stiripentol in the treatment of U.S. children with Dravet syndrome.
METHODS: U.S. clinicians who had prescribed stiripentol for two or more children with Dravet syndrome between March 2005 and 2012 were contacted to request participation in this retrospective study. Data collected included overall seizure frequency, frequency of prolonged seizures, and use of rescue medications and emergency room (ER)/hospital visits in the year preceding stiripentol initiation, and with stiripentol therapy. We separately assessed efficacy in the following treatment groups: group A, stiripentol without clobazam or valproate; group B, stiripentol with clobazam but without valproate; group C, stiripentol with valproate but without clobazam; and group D, stiripentol with clobazam and valproate. In addition, adverse effects were recorded.
RESULTS: Thirteen of 16 clinicians contacted for study participated and provided data on 82 children. Stiripentol was initiated a median of 6.0 years after seizure onset and 1.2 years after diagnosis of Dravet syndrome. Compared to baseline, overall seizure frequency was reduced in 2/6 in group A, 28/35 in group B, 8/14 in group C, and 30/48 in group D. All children with prolonged seizure frequency greater than quarterly during the baseline period experienced a reduction in this frequency on the various treatment arms with stiripentol. Similarly, 2/4 patients in group A, 25/25 in group B, 5/10 in group C, and 26/33 in group D experienced reduction in frequency of rescue medication use and 1/1 in group A, 12/12 in group B, 3/5 in group C, and 18/19 in group D had reduction in frequency of ER/hospital visits. Adverse effects were reported in 38, most commonly sedation and reduced appetite. Four patients (5%) discontinued stiripentol for adverse effects and two (2%) for lack of efficacy.
CONCLUSIONS: Stiripentol is an effective and well-tolerated therapy that markedly reduced frequency of prolonged seizures in Dravet syndrome.