Stiripentol kinetics during oral therapy were assessed in six 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 (mean +/- SD), greater than that at 1200 mg/day (20.3 +/- 8.8 l/day/kg; P less than 0.05) or 2400 mg/day (8.5 +/- 3.8 l/day/kg; P less than 0.01). The apparent in vivo Michaelis-Menten parameters were determined from three 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 five 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 less than 0.01). Stiripentol reduced the clearance of carbamazepine in one 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 two 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 its interactions with other antiepileptic drugs, have important implications in the designing of controlled clinical trials.

Administration, Oral↗

PubMed1984

Michaelis-Menten kinetics of stiripentol in normal humans.

Michaelis-Menten kinetic parameters for stiripentol, and anticonvulsant, were assessed in six normal volunteers. Stiripentol was administered orally three times a day in dosage increments of 600, 1,200, and 1,800 mg/day for consecutive periods of 3, 4, and 7 days, respectively. Stiripentol steady-state levels at the three dosing rates increased more than proportionally with dose. The mean +/- SD oral clearance of stiripentol at 600 mg/day (1,090 +/- 624 L/day) was significantly greater (p less than 0.01) than at 1,200 (506 +/- 219 L/day) or 1,800 (405 +/- 151 L/day) mg/day. Average steady-state concentrations predicted from individually determined Vm and Km parameters were in good agreement with experimentally observed levels, indicating that the kinetics of stiripentol are of the Michaelis-Menten type. The mean Vm, Km, and Vm/Km ratio were 2,299 +/- 490 mg/day, 2.20 +/- 1.28 mg/L, and 1,241 +/- 837 L/day, respectively. Neuropsychological tests carried out before and after 14 days of stiripentol treatment showed a significant decline in verbal learning ability (p = 0.038) and a significant improvement in a test of memory and attention (p less than 0.01).

Adult↗

PubMed1983