Pharmacokinetics of Stiripentol in Normal Man: Evidence of Nonlinearity

Abstract

The pharmacokinetics and metabolism of stiripentol, a new antiepileptic drug, were investigated in normal male subjects after single-dose and multiple-dose administration. Each of six subjects received single doses of 300, 600, and 1200 mg of stiripentol in powder form and another 600 mg in solution. In the multiple-dose study, each of six subjects received a 300-mg dose on day 1 and multiple doses (1200 mg/day) from day 2 to day 8. Five of these six subjects participated also in the single-dose study. Stiripentol and several of its metabolites, namely, stiripentol conjugate, DiOH, P-OH, and M-OH, were analyzed in plasma and urine. After single doses, the elimination curve of stiripentol appeared multiphasic. The oral clearance was 1.3 to 1.8 liter/hr/kg. The average mean residence time was 4 hours. There were no statistically significant differences in clearance or mean residence time among the three doses. However, dose dependence was found in all the four pathways when formation clearances were compared. Only trace amounts of the drug were excreted unchanged in urine. The active metabolite, P-OH, was not detectable in plasma. Stiripentol was very highly bound to plasma proteins in plasma from dosed subjects as well as spiked human plasma (free fraction of 1 per cent). In the multiple-dose study, there was a decrease (nearly eightfold) in oral clearance of stiripentol between day 1 and day 8. The fractions of dose metabolized through conjugation and methylenedioxy ring opening increased 183 and 49 per cent, respectively, but the formation clearances for all the pathways were decreased. These findings suggest that the steady-state plasma level/dose ratio of stiripentol will increase with the daily dose.

Therapeutic Drug Monitoring of Classical and Newer Anticonvulsants

“…There is non-linear clearance of the drug with decreasing clearance while increasing the dosage, consistent with Michaelis-Menten kinetics [114]. Urinary clearance of the unchanged drug is less than 4%, and 16e22% is excreted in the urine as conjugates [115]. Stiripentol is highly protein bound at 99%, leaving only the unbound 1% of the drug able to act on the GABA receptors [115].…”

A Case of Dravet Syndrome Who Developed Acute Reversible Encephalopathy That May Have Been Caused by Hyperamonnemia Due to Pharmacokinetic Interaction Between Valproate and Stiripentol

“…[9,10] STP oral olarak alındıktan sonra 1.5 saatte plazma pik konsantrasyonuna ulaşır. [11] Suda iyi çözünür, karaciğerde ilk geçiş etkisine maruz kalır, biyoyararlanımı rölatif olarak düşüktür. %99 plazma proteinlerine bağlanır.…”

“…Verilen dozun 12 saat sonra %18'i feçesten, %73'ü idrardan geri alınır. [11][12][13] Bilinen 5 metabolizma yolu vardır: 1) Glukuronik asit ile konjugasyon, 2) Metilendioksi halka sisteminin oksidatif olarak kırılması, 3) Katekol metabolitlerinin o-metilasyonu 4) t-butil grubunun hidroksilasyonu, 5) Alil aklol zincirinin isomerik 3-pentaton yapısına çevrilmesi. [14][15][16] STP transformasyonunda en önemli basamak metilendioksi halkasının katekol derivelerini oluştur-mak üzere açılmasıdır.…”

Therapeutic Drug Monitoring of Antiepileptic Medications

“…The hepatic metabolism of stiripentol is very complex, with at least 5 different metabolic pathways generating over a dozen metabolites. The dosing of stiripentol is further complicated by zero-order (saturation) elimination kinetics, with a marked decrease in clearance with increased dosage (Levy et al, 1983). Stiripentol is also highly (>99%) protein bound and prone to drug interactions that can alter the free fraction (Lacerda et al, 2006).…”

“…Measurement of the free drug fraction of stiripentol may be clinically useful; however, methods to measure free fractions have not yet been reported. When used in combination AEM therapies, stiripentol may cause drug-drug interactions by inhibiting the metabolism of carbamazepine, clobazam, phenobarbital, phenytoin, and valproic (Levy et al, 1984;Tran et al, 1997;Tran et al, 1996).…”