Use Of Stiripentol Research Articles

Use of Stiripentol in Patients with Dravet Syndrome: Common Practice Among Experts in Spain.

Despite considerable evidence for the efficacy and safety of stiripentol in Dravet syndrome (DS), some aspects of stiripentol use remain challenging in clinical practice, such as dose titration and the adjustment of concomitant antiseizure medications (ASMs) to prevent potential adverse effects. To (1) provide practical recommendations on the initiation of stiripentol treatment in patients with DS, (2) evaluate its effectiveness in the patient, and (3) guide the management of drug interactions and other aspects of treatment monitoring. Six Spanish neurologists (the authors) with expertise in the management of pediatric and adult patients with DS held a meeting in early 2024 to develop expert recommendations regarding the use of stiripentol in DS, based on a review of the literature and their common clinical experience. According to these recommendations, stiripentol can be administered to patients with DS of any age, although its initiation and titration vary according to age group. Individualized adjustment of concomitant ASMs, such as valproic acid and clobazam or drugs specifically for DS (i.e., fenfluramine), at initiation and during stiripentol treatment, can mitigate drug interactions, thereby increasing the long-term tolerability of stiripentol treatment. In specific cases, stiripentol doses of>50 mg/kg/day may be contemplated, and acute stiripentol administration may be considered to control refractory status epilepticus. Blood tests should be performed before starting stiripentol, at 3, 6, and 12 months after starting treatment, and then annually, except in the event of adverse effects, when additional testing may be necessary. Most adverse effects can be adequately managed by adjusting concomitant medications. These practical recommendations may be easily adapted for use in different countries, and should increase physicians' confidence in the initiation and monitoring of stiripentol treatment, thus facilitating effective management of patients with DS and improving clinical outcomes.

Stiripentol add-on therapy for drug-resistant focal epilepsy.

This is an updated version of the Cochrane Review first published in 2014 and last updated in 2020. For nearly 30% of people with epilepsy, current treatments do not control seizures. Stiripentol is an antiepileptic drug (AED) that was developed in France and was approved by the European Medicines Agency (EMA) in 2007 as an adjunctive therapy with valproate and clobazam for the treatment of Dravet syndrome. To evaluate the efficacy and tolerability of stiripentol as add-on treatment for people with drug-resistant focal epilepsy who are taking AEDs. For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE on 28 March 2022. We contacted the manufacturer of stiripentol and epilepsy experts to identify published, unpublished and ongoing trials. Randomised controlled trials of add-on stiripentol in people with drug-resistant focal epilepsy. Review authors independently selected trials for inclusion and extracted data. We investigated outcomes including 50% or greater reduction in seizure frequency, seizure freedom, adverse effects, treatment withdrawal and changes in quality of life. On the basis of our selection criteria, we included no new studies in the present review update. We included only one study from the original review (32 children with focal epilepsy). This study adopted a responder-enriched design and found no clear evidence of a reduction of 50% or more in seizure frequency (risk ratio (RR) 1.51, 95% confidence interval (CI) 0.81 to 2.82; low-certainty evidence) and no clear evidence of seizure freedom (RR 1.18, 95% CI 0.31 to 4.43; low-certainty evidence) when comparing add-on stiripentol with placebo. Stiripentol led to a greater risk of adverse effects considered as a whole (RR 2.65, 95% CI 1.08 to 6.47; low-certainty evidence). When we considered specific adverse effects, CIs were very wide and showed the possibility of substantial increases and small reductions in risks of neurological adverse effects (RR 2.65, 95% CI 0.88 to 8.01; low-certainty evidence). Researchers noted no clear reduction in the risk of study withdrawal (RR 0.66, 95% CI 0.30 to 1.47; low-certainty evidence), which was high in both groups (53.3% in placebo group and 35.3% in stiripentol group; low-certainty evidence). The external validity of this study was limited because only responders to stiripentol (i.e. participants experiencing a decrease in seizure frequency of 50% or greater during an open prerandomisation phase compared with baseline) were included in the randomised, add-on, placebo-controlled, double-blind phase. Furthermore, carry-over and withdrawal effects probably influenced outcomes related to seizure frequency. Very limited information derived from the only included study shows that adverse effects considered as a whole may occur more often with add-on stiripentol than with add-on placebo. We have found no new studies since the last version of this review was published. Hence, we have made no changes to the conclusions as presented in previous versions. We can draw no conclusions to support the use of stiripentol as add-on treatment for drug-resistant focal epilepsy. Additional large, randomised, well-conducted trials are needed.

Effet du stiripentol sur l’excrétion urinaire d’oxalate

Oxalate is a metabolite promoting the formation of calcium oxalate crystals in urine. Hyperoxaluria is a feature of genetic diseases, known as primary hyperoxaluria, leading to chronic kidney disease. Ethylene glycol poisoning induces the crystallization of calcium oxalate crystals in renal tubules, promoting acute renal failure. Urine oxalate results from glyoxylate transformation to oxalate in the liver, due to lactate dehydrogenase (LDH) activity, especially the LDH-5 isoenzyme. Genetic RNA interference therapy targeting lactate dehydrogenase lowers urine oxalate excretion in murine models. Stiripentol is a drug inhibiting neuronal LDH-5 isoenzyme activity. We hypothesized that stiripentol would also reduce hepatic oxalate production and urine oxalate excretion. In vitro Stiripentol decreases oxalate synthesis by hepatocytes. In vivo, stiripentol decreases urine oxalate excretion in rats and protects kidney tissue and function against ethylene glycol intoxication and hydroxyproline-induced calcium oxalate crystalline nephropathy. The use of stiripentol in clinical practice deserves further clinical studies.

Stiripentol identifies a therapeutic target to reduce oxaluria.

Oxalate is a metabolic end-product promoting the formation of calcium oxalate crystals in urine. Massive urine oxalate excretion occurs in genetic diseases, mainly primary hyperoxaluria type I and II, threatening renal function. Ethylene glycol poisoning may induce the precipitation of calcium oxalate crystals in renal tubules, leading to acute renal failure. In both cases, oxalate results from glyoxylate transformation to oxalate in the liver, by lactate dehydrogenase (LDH) enzymes, especially the LDH-5 isoenzyme. The purpose of the review is to highlight LDH as a potential therapeutic target according to recent publications. Genetic therapy targeting LDH metabolism decreases urine oxalate excretion in rodents. Stiripentol is an antiepileptic drug that has been shown recently to inhibit neuronal LDH-5 isoenzyme. Stiripentol was hypothesized to reduce hepatic oxalate production and urine oxalate excretion. In vitro, stiripentol decreases oxalate synthesis by hepatocytes. In vivo, stiripentol oral administration decreases urine oxalate excretion in rats and protects renal function and renal tissue against ethylene glycol intoxication and chronic calcium oxalate crystalline nephropathy. The use of stiripentol in-vitro and in-vivo highlights that targeting hepatic LDH by pharmacological or genetic tools may decrease oxalate synthesis, deserving clinical studies.

Stiripentol add-on therapy for drug-resistant focal epilepsy.

This is an updated version of the Cochrane Review first published in 2014, and last updated in 2018. For nearly 30% of people with epilepsy, seizures are not controlled by current treatments. Stiripentol is an antiepileptic drug (AED) that was developed in France and was approved by the European Medicines Agency (EMA) in 2007 for the treatment of Dravet syndrome as an adjunctive therapy with valproate and clobazam. To evaluate the efficacy and tolerability of stiripentol as add-on treatment for people with drug-resistant focal epilepsy who are taking AEDs. For the latest update, we searched the following databases on 27 February 2020: Cochrane Register of Studies (CRS Web); and MEDLINE (Ovid, 1946 to 26 February 2020). CRS Web includes randomised or quasi-randomised controlled trials from the Specialized Registers of Cochrane Review Groups including Epilepsy, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (ICTRP). We contacted Biocodex (the manufacturer of stiripentol) and epilepsy experts to identify published, unpublished and ongoing trials. Randomised, controlled, add-on trials of stiripentol in people with drug-resistant focal epilepsy. Review authors independently selected trials for inclusion and extracted data. We investigated outcomes including 50% or greater reduction in seizure frequency, seizure freedom, adverse effects, treatment withdrawal and changes in quality of life. On the basis of our selection criteria, we included no new studies in the present review update. We included only one study from the earlier review (32 children with focal epilepsy). This study adopted a responder-enriched design and found no clear evidence of a reduction in seizure frequency (≥ 50% seizure reduction) (risk ratio (RR) 1.51, 95% confidence interval (CI) 0.81 to 2.82; low-certainty evidence) or evidence of seizure freedom (RR 1.18, 95% CI 0.31 to 4.43; low-certainty evidence) when add-on stiripentol was compared with placebo. Stiripentol led to a greater risk of adverse effects considered as a whole (RR 2.65, 95% CI 1.08 to 6.47; low-certainty evidence). When we considered specific adverse events, confidence intervals were very wide and showed the possibility of substantial increases and small reductions in risks of neurological adverse effects (RR 2.65, 95% CI 0.88 to 8.01; low-certainty evidence) and gastrointestinal adverse effects (RR 11.56, 95% CI 0.71 to 189.36; low-certainty evidence). Researchers noted no clear reduction in the risk of study withdrawal (RR 0.66, 95% CI 0.30 to 1.47; low-certainty evidence), which was high in both groups (35.0% in add-on placebo and 53.3% in stiripentol group; low-certainty evidence). The external validity of this study was limited because only responders to stiripentol (i.e. patients experiencing a ≥ 50% decrease in seizure frequency compared with baseline) were included in the randomised, add-on, placebo-controlled, double-blind phase. Furthermore, carry-over and withdrawal effects probably influenced outcomes related to seizure frequency. Very limited information derived from the only included study shows that adverse effects considered as a whole seemed to occur significantly more often with add-on stiripentol than with add-on placebo. We have found no new studies since the last version of this review was published. Hence, we have made no changes to the conclusions of this update as presented in the initial review. We can draw no conclusions to support the use of stiripentol as add-on treatment for drug-resistant focal epilepsy. Additional large, randomised, well-conducted trials are needed.

Stiripentol add-on therapy for focal refractory epilepsy.

This is an updated version of the Cochrane review last published in 2015 (Issue 10). For nearly 30% of people with epilepsy, seizures are not controlled by current treatments. Stiripentol is a new antiepileptic drug (AED) that was developed in France and was approved by the European Medicines Agency (EMA) in 2007 for the treatment of Dravet syndrome as an adjunctive therapy with valproate and clobazam, with promising effects. To evaluate the efficacy and tolerability of stiripentol as add-on treatment for people with focal refractory epilepsy who are taking AEDs. For the latest update, we searched the following databases on 21 August 2017: Cochrane Epilepsy Specialized Register, CENTRAL , MEDLINE, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP). We contacted Biocodex (the manufacturer of stiripentol) and epilepsy experts to identify published, unpublished and ongoing trials. Randomised, controlled, add-on trials of stiripentol in people with focal refractory epilepsy. Review authors independently selected trials for inclusion and extracted data. Outcomes investigated included 50% or greater reduction in seizure frequency, seizure freedom, adverse effects, treatment withdrawal and changes in quality of life. On the basis of our selection criteria, we included no new studies in the present review. Only one study was included from the earlier review (32 children with focal epilepsy). This study adopted a 'responder enriched' design and found no clear evidence of a reduction in seizure frequency (≥ 50% seizure reduction) (risk ratio (RR) 1.51, 95% confidence interval (CI) 0.81 to 2.82, low-quality evidence) nor evidence of seizure freedom (RR 1.18, 95% CI 0.31 to 4.43, low-quality evidence) when add-on stiripentol was compared with placebo. Stiripentol led to a greater risk of adverse effects considered as a whole (RR 2.65, 95% CI 1.08 to 6.47, low-quality evidence). When specific adverse events were considered, confidence intervals were very wide and showed the possibility of substantial increases and small reductions in risks of neurological (RR 2.65, 95% CI 0.88 to 8.01, low-quality evidence) or gastrointestinal adverse effects (RR 11.56, 95% CI 0.71 to 189.36, low-quality evidence). Researchers noted no clear reduction in the risk of study withdrawal (RR 0.66, 95% CI 0.30 to 1.47, low-quality evidence), which was high in both groups (35.0% in add-on placebo and 53.3% in stiripentol group, low-quality evidence). The external validity of this study was limited because only responders to stiripentol (i.e. patients experiencing a ≥ 50% decrease in seizure frequency compared with baseline) were included in the randomised, add-on, placebo-controlled, double-blind phase. Furthermore, carry-over and withdrawal effects probably influenced outcomes related to seizure frequency. Very limited information derived from the only included study shows that adverse effects considered as a whole seemed to occur significantly more often with add-on stiripentol than with add-on placebo. Since the last version of this review was published, we have found no new studies. Hence, we have made no changes to the conclusions of this update as presented in the initial review. We can draw no conclusions to support the use of stiripentol as add-on treatment for focal refractory epilepsy. Additional large, randomised, well-conducted trials are needed.

Long-term pragmatic use of stiripentol for Dravet syndrome.

This commentary is on the original article by Myers et al. on pages 574–578 of this issue.

Effect of CYP Inducers/Inhibitors on Topiramate Concentration: Clinical Value of Therapeutic Drug Monitoring.

This study investigated the pharmacokinetic interactions between topiramate (TPM) and concomitant antiepileptic drugs and evaluated the therapeutic concentration range of TPM and the effect of the achieved plasma concentration on the retention rate of TPM therapy. A total of 1217 plasma samples obtained from 610 patients were retrospectively investigated, and the concentration-to-dose ratio (CD ratio) of TPM was compared among patients on various antiepileptic drug regimens. In addition, the therapeutic concentration of TPM was reviewed in patients on long-term therapy, and factors influencing the retention rate of TPM were analyzed by the Kaplan-Meier method. Among patients using hepatic enzyme inducers (phenytoin, phenobarbital, and carbamazepine), the CD ratio was reduced by 45.4% in adults and 33.3% in children. Patients taking phenytoin concomitantly had a significantly lower CD ratio than patients taking phenobarbital or carbamazepine. Among noninducers, concomitant use of stiripentol increased the CD ratio. In 276 patients who remained on TPM therapy for more than 2 years, the mean therapeutic concentration was 5.1 mcg/mL (15.0 μmol/L). The estimated retention day was significantly higher for patients with a TPM concentration >5 mcg/mL than that for patients with a concentration <5 mcg/mL (945 versus 802 days; P = 0.007 by the log-rank test). Also, patients without hepatic enzyme inducers had a significantly higher retention rate than patients using such inducers (P = 0.002). Concomitant use of hepatic enzyme inducers markedly reduced the plasma TPM concentration and can decrease its antiepileptic effect. A therapeutic concentration of >5 mcg/mL TPM was significantly associated with continuation of therapy, and therapeutic drug monitoring can be helpful.

Audit of use of stiripentol in adults with Dravet syndrome.

ObjectivesThere are very few data available in the literature on the use of stiripentol in adults with Dravet syndrome (DS). DS cases are increasingly recognized in adulthood, and more children with DS now survive to adulthood. The aim of the study was to document the effectiveness and tolerability of stiripentol in adults with DS.Material and methodsWe conducted an observational clinical audit in the epilepsy service of the National Hospital for Neurology and Neurosurgery, London (UK).ResultsWe included 13 adult subjects with DS (eight females, five males). The responder (defined as more than 50% reduction in all seizure types) rate was 3/13 (23%) at 36 months. The following other outcomes were reported: seizure exacerbation (3/13, 23%), no change (3/13, 23%), less than 50% reduction in seizures (2/13, 15%), more than 50% reduction in generalized tonic‐clonic seizures but no other seizure types (1/13, 8%), undefined response (1/13, 8%). The retention rate was 62% after 1 year and 31% after 5 years. Adverse effects were reported in 7/13 (54%): the most frequent were anorexia, weight loss, unsteadiness and tiredness. Withdrawal due to adverse effects occurred in 3/13 (23%).ConclusionsCompared with previous studies on children with DS, our results show a lower responder rate and a similar tolerability profile. Stiripentol can be effective with a good tolerability profile. Our audit is small, but supports the use of stiripentol in adults with DS when first‐line treatments are ineffective or not tolerated, in keeping with published guidelines.

Pharmacological considerations in the use of stiripentol for the treatment of epilepsy

ABSTRACTIntroduction: Despite the fact that more than 20 antiepileptic drugs (AEDs) are currently available, about one-third of patients still present drug resistance. Further efforts are required to develop novel and more efficacious therapeutic strategies, especially for refractory epileptic syndromes showing few and anecdotic therapeutic options.Areas covered: Stiripentol (STP) is a second generation AED that shows GABAergic activity, with immature brain selectivity, and an indirect metabolic action on co-administered AEDs. Two pivotal studies demonstrated STP efficacy in patients with Dravet syndrome with refractory partial seizures, and marketing authorization in Europe, Canada and Japan was granted thereafter. Post-marketing surveys reported a good efficacy and tolerability profile. In addition, interesting data is currently emerging regarding off-label experimentation of STP in other forms of epilepsy.Expert opinion: STP is an important addition to the limited treatment options available for patients resistant to common AEDs. The possibility to inhibit seizures through the metabolic pathway of lactate dehydrogenase and the inhibitory effects on the entry of Na+ and Ca2+ are the most recent findings to emerge about STP and could be proof of its neuroprotective action. Moreover, its positive effects on cognitive function, its good safety and tolerability profile and the increasing data about STP efficacy on other refractory epileptic syndromes may prove to be fertile grounds for further investigation.

Stiripentol for focal refractory epilepsy.

This is an updated version of the original Cochrane review published in 2014 (Issue 1). For nearly 30% of people with epilepsy, seizures are not controlled by current treatments. Stiripentol is a new antiepileptic drug (AED) that was developed in France and was approved by the European Medicines Agency (EMA) in 2007 for the treatment of Dravet syndrome as adjunctive therapy with valproate and clobazam, with promising effects. To evaluate the efficacy and tolerability of stiripentol as add-on treatment for patients with focal refractory epilepsy who are taking AEDs. We searched the Cochrane Epilepsy Group Specialised Register (10 August 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; August 2015, Issue 8)and MEDLINE (Ovid) (1946 to 10 August 2015). We contacted Biocodex (the manufacturer of stiripentol) and epilepsy experts to identify published, unpublished and ongoing trials. Randomised controlled add-on trials of stiripentol in patients with focal refractory epilepsy. Review authors independently selected trials for inclusion and extracted data. Outcomes investigated included 50% or greater reduction in seizure frequency, seizure freedom, adverse effects, treatment withdrawal and changes in quality of life. On the basis of our selection criteria, we included no new studies in the present review. However, we did include one study from the earlier review (32 children with focal epilepsy). This study adopted a 'responder enriched' design and found no clear evidence of a reduction in seizure frequency (≥ 50% seizure reduction) (risk ratio (RR) 1.51, 95% confidence interval (CI) 0.81 to 2.82) nor evidence of seizure freedom (RR 1.18, 95% CI 0.31 to 4.43) when add-on stiripentol was compared with placebo. Stiripentol led to a greater risk of adverse effects considered as a whole (RR 2.65, 95% CI 1.08 to 6.47). When specific adverse events were considered, confidence intervals were very wide and showed the possibility of substantial increases and small reductions in risks of neurological (RR 2.65, 95% CI 0.88 to 8.01) or gastrointestinal adverse effects (RR 11.56, 95% CI 0.71 to 189.36). Researchers noted no clear reduction in the risk of study withdrawal (RR 0.66, 95% CI 0.30 to 1.47), which was high in both groups (35.0% in add-on placebo and 53.3% in stiripentol group). The external validity of this study was limited because only responders to stiripentol (i.e. patients experiencing a ≥ 50% decrease in seizure frequency compared with baseline) were included in the randomised add-on placebo-controlled double-blind phase. Furthermore, carry-over and withdrawal effects probably influenced outcomes related to seizure frequency. Very limited information derived from the only included study shows that adverse effects considered as a whole seemed to occur significantly more often with add-on stiripentol than with add-on placebo. Since the last version of this review was published, we have found no new studies. Hence, we have made no changes to the conclusions of this update as presented in the initial review. We can draw no conclusions to support the use of stiripentol as add-on treatment for focal refractory epilepsy. Additional large, randomised, well-conducted trials are needed.

Extending the use of stiripentol to other epileptic syndromes: A case of PCDH19-related epilepsy

Stiripentol is an antiepileptic drug (AED) approved by the European Medicines Agency for the treatment of Dravet Syndrome (DS) as adjunct treatment with valproate and clobazam.PCDH19-related epilepsy is an emerging epileptic syndrome characterized by the occurrence of epilepsy in female patients associated with mental retardation and autistic features in most cases. It shares many features with DS: age of onset, normal development before the onset, fever sensitivity, cognitive impairment during the time, drug-resistance. Basing on the numerous similarities between DS and PCDH19-related epilepsy, we tried stiripentol in a nine and half year old female patient with PCDH19-related resistant epilepsy, as add-on treatment to valproate and clobazam. It had a surprising efficacy as the patient had a two years and ten months seizure free period, as never in her epilepsy history.Up to date, clinical trials of stiripentol have been always focused on DS. The delineation of new epileptic syndromes, as PCDH19-related epilepsy, opens new scenarios to the utilization of this AED. This case report is suggestive of a good response of PCDH19-related Epilepsy to stiripentol. However further cases and above all clinical trials are necessary to confirm this result.

Impact of cytochrome P450 inducers with or without inhibitors on the serum clobazam level in patients with antiepileptic polypharmacy.

The aim of this study was to evaluate the effect of cytochrome P450 (CYP) inducers/inhibitors on the pharmacokinetics of clobazam (CLB) in patients receiving antiepileptic polypharmacy. A total of 2,504 samples obtained from 1,280 patients for routine therapeutic drug monitoring were retrospectively reviewed. These samples were grouped according to the antiepileptic drug regimens or age, and then the concentration to dose (CD) ratio (serum level (ng/ml) divided by dose (mg/kg)) of CLB was calculated for comparison. The mean CD ratio of CLB in adult patients using enzyme inducers (phenytoin (PHT), carbamazepine (CBZ), and phenobarbital (PB) alone or in combination) was 60.8% lower than the ratio in patients without inducers. Among the inducers, patients using PHT had a significantly lower CD ratio than patients using PB or CBZ (p < 0.001). When PHT was combined with CBZ and/or PB, no additive or synergetic interactions was observed. The CD ratio of CLB in pediatric patients using inducers was 44.3% lower than in patients without inducers. The influence of inducers was unchanged regardless of the child's age, and the effect was stronger in adults than in pediatric patients. Other than inducers, valproic acid (VPA) additively reduced the CD ratio, whereas concomitant use of stiripentol significantly elevated the CD ratio in patients receiving VPA. In contrast, CYP3A4 substrates, such as zonisamide and topiramate, had little influence on the CD ratio of CLB. We identified an impact of CYP inducers/inhibitors on the CLB concentration. Our findings demonstrated that clinically relevant interactions occur between CLB and concomitant antiepileptic drugs.