Stiripentol kinetics in epilepsy: Nonlinearity and interactions

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Abstract
Stiripentol kinetics during oral therapy were assessed in 6 patients with epilepsy who were receiving other antiepileptic drugs. Steady-state levels at 600, 1200, and 2400 mg/day increased in a nonlinear fashion, indicating Michaelis-Menten kinetics. Oral clearance of stiripentol at 600 mg/day was 41.5 .+-. 23.4 l/day/kg (.hivin.X [mean] .+-. SD), greater than that at 1200 mg/day (20.3 .+-. 8.8 l/day/kg; P < 0.05) or 2400 mg/day (8.5 .+-. 3.8 l/day/kg; P < 0.01). The apparent in vivo Michaelis-Menten parameters were determined from 3 mean steady-state concentrations. The average velocity of conversion of stiripentol to its metabolites (Vm), Michaelis constant (Km), and the ratio Vm/Km were 49.3 .+-. 13.1 mg/day/kg, 1.35 .+-. 1.08 mg/l, and 50.2 .+-. 27.5 l/day/kg. Stiripentol reduced the elimination clearances of concomitant antiepileptic drugs. Phenytoin clearance was reduced in all 5 subjects who received this drug, from a mean control of 29.5 .+-. 13.4 l/day to 18.5 .+-. 4.6 l/day at a stiripentol dose of 1200 mg/day (P = 0.05) and to 6.48 .+-. 2.59 l/day at 2400 mg/day (P < 0.01). Stiripentol reduced the clearance of carbamazepine in 1 subject from a control value of 209 l/day to 128 l/day (1200 mg/day) and 61 l/day (2400 mg/day). Stiripentol reduced phenobarbital clearance in 2 subjects from 3.8 and 5.1 l/day to 2.3 and 3.4 l/day (2400 mg/day). The Michaelis-Menten kinetics of stiripentol, as well as it interactions with other antiepileptic drugs, have important implications in the designing of controlled clinical trials.