Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Biocodex, 7 Avenue Gallieni, 94250, Gentilly, France
Pharmacotherapeutic group: Antiepileptics, other antiepileptics
ATC code: N03AX17
In animal models, stiripentol antagonizes seizures induced by electric shock, pentetrazole and bicuculline. In rodent models, stiripentol appears to increase brain levels of gamma-aminobutyric acid (GABA) - the major inhibitory neurotransmitter in mammalian brain. This could occur by inhibition of synaptosomal uptake of GABA and/or inhibition of GABA transaminase. Stiripentol has also been shown to enhance GABAA receptor-mediated transmission in the immature rat hippocampus and increase the mean open-duration (but not the frequency) of GABAA receptor chloride channels by a barbiturate-like mechanism.
Stiripentol potentiates the efficacy of other anticonvulsants, such as carbamazepine, sodium valproate, phenytoin, phenobarbital and many benzodiazepines, as the result of pharmacokinetic interactions. The second effect of stiripentol is mainly based on metabolic inhibition of several isoenzymes, in particular CYP450 3A4 and 2C19, involved in the hepatic metabolism of other anti-epileptic medicines. h2. Clinical efficacy and safety.
The pivotal clinical evaluation of stiripentol was in children of 3 years of age and over with SMEI.
A French compassionate use program included children from 6 months of age because the diagnosis of Dravet’s syndrome may be made with confidence at that age in some patients. The clinical decision for use of Diacomit in children with SMEI less than 3 years of age needs to be made on an individual patient basis taking into consideration the potential clinical benefits and risks (see section 4.2). 41 children with SMEI were included in a randomised, placebo-controlled, add-on trial. After a baseline period of 1 month, placebo (n=20) or stiripentol (n=21) was added to valproate and clobazam during a double-blind period of 2 months. Patients then received stiripentol in an open fashion. Responders were defined as having more than 50% reduction in the frequency of clonic (or tonicclonic) seizures during the second month of the double-blind period compared with baseline. 15 (71%) patients were responders on stiripentol (including nine free of clonic or tonic-clonic seizures), whereas there was only one (5%) on placebo (none was seizure free; stiripentol 95% CI 52.1-90.7 vs. placebo 0-14.6). The 95% CI of the difference was 42.2-85.7. Percentage of change from baseline was higher on stiripentol (-69%) than on placebo (+7%), p<0.0001. 21 patients on stiripentol had moderate side-effects (drowsiness, loss of appetite) compared with eight on placebo, but side-effects disappeared when the dose of comedication was decreased in 12 of the 21 cases (Chiron et al, Lancet, 2000).
There are no clinical study data to support the clinical safety of stiripentol administered at daily doses greater than 50 mg/kg/day. There are no clinical study data to support the use of stiripentol as monotherapy in Dravet’s syndrome.
The following pharmacokinetic properties of stiripentol have been reported from studies in adult healthy volunteers and adult patients.
Stiripentol is quickly absorbed, with a time to peak plasma concentration of about 1.5 hours. The absolute bioavailability of stiripentol is not known since an intravenous formulation is not available for testing. It is well absorbed by the oral route since the majority of an oral dose is excreted in urine.
Relative bioavailability between the capsules and powder for oral suspension in sachet formulations has been studied in healthy male volunteers after a 1,000 mg single oral administration. The two formulations were bioequivalent in terms of AUC but not in terms of Cmax. Cmax of the sachet was slightly higher (23%) compared with the capsule and did not meet the criteria for bioequivalence. Tmax was similar with both formulations. Clinical supervision is recommended if switching between the stiripentol capsule and powder for oral suspension in sachet formulations.
Stiripentol binds extensively to circulating plasma proteins (about 99%).
Systemic exposure to stiripentol increases markedly compared to dose proportionality. Plasma clearance decreases markedly at high doses; it falls from approximately 40 l/kg/day at the dose of 600 mg/day to about 8 l/kg/day at the dose of 2,400 mg. Clearance is decreased after repeated administration of stiripentol, probably due to inhibition of the cytochrome P450 isoenzymes responsible for its metabolism. The half-life of elimination was in the range of 4.5 hours to 13 hours, increasing with dose.
Stiripentol is extensively metabolized, 13 different metabolites having been found in urine. The main metabolic processes are demethylenation and glucuronidation, although precise identification of the enzymes involved has not yet been achieved. On the basis of in vitro studies, the principal liver cytochrome P450 isoenzymes involved in phase 1 metabolism are considered to be CYP1A2, CYP2C19 and CYP3A4.
Most stiripentol is excreted via the kidney. Urinary metabolites of stiripentol accounted collectively for the majority (73%) of an oral acute dose whereas a further 13-24% was recovered in faeces as unchanged substance.
A population pharmacokinetic study was conducted in 35 children with Dravet Syndrome treated with stiripentol and two substances not known to affect stiripentol pharmacokinetics, valproate and clobazam. The median age was 7.3 years (range: 1 to 17.6 years) and the median daily dose of stiripentol was 45.4 mg/kg/day (range: 27.1 to 89.3 mg/kg/day) received in two or three divided doses.
The data were best fitted with a one compartment model with first order absorption and elimination processes. The population estimate for the absorption rate constant Ka was 2.08 hr-1 (standard deviation of random effect = 122%). Clearance and volume of distribution were related to body weight by an allometric model with exponents of 0.433 and 1, respectively: as body weight increased from 10 to 60 kg, apparent oral clearance increased from 2.60 to 5.65 L/hr and apparent volume of distribution increased from 32.0 to 191.8 L. As a result, elimination half-life increased from 8.5hr (for 10 kg) to 23.5 hr (for 60 kg).
Toxicity studies in animals (rat, monkey, mouse) have not revealed any consistent pattern of toxicity apart from liver enlargement associated with hepatocellular hypertrophy, which occurred when high doses of stiripentol were administered to both rodents and non-rodents. This finding is considered to be an adaptive response to a high metabolic burden on the liver.
Stiripentol was not teratogenic when tested in the rat and rabbit; in one study in the mouse, but not in several other similar studies, a low incidence of cleft palate formation was observed at a maternotoxic dose (800 mg/kg/day). These studies in mice and rabbits were undertaken prior to the introduction of Good Laboratory Practice requirements. Studies in the rat on fertility and general reproductive performance and on pre- and postnatal development were uneventful except for a minor reduction in the survival of pups nursed by mothers exhibiting toxic responses to stiripentol at a dose of 800 mg/kg/day (see section 4.6).
Genotoxicity studies have not detected any mutagenic or clastogenic activity. Carcinogenicity studies gave negative results in the rat. In the mouse there was only a small increase in the incidence of hepatic adenomas and carcinomas in animals treated with 200 or 600 mg/kg/day for 78 weeks but not in those given 60 mg/kg/day. In view of the lack of genotoxicity of stiripentol and the well-known, special susceptibility of the mouse liver to tumour formation in the presence of hepatic enzyme induction, this finding is not considered to indicate a risk of tumorigenicity in patients.
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