Pharmacokinetics of midazolam and metabolites in a patient with refractory status epilepticus treated with extraordinary doses of midazolam

The authors present a patient with refractory epilepsy who was treated with very high doses (up to 4 mg/min) of intravenous midazolam, phenytoin, carbamazepine, and other antiepileptics. Because it was known from the literature that the half-life of midazolam can increase at high dosage, the kinetics of midazolam (MDZ), 1'-hydroxymidazolam, and 4-hydroxymidazolam were assessed at steady state (dosage 1 mg/min) and after stopping treatment. Total body clearance of MDZ (33 L/kg) and intrinsic hepatic clearance (19 mL/min/kg) at steady state were both five to 10 times higher than after normal therapeutic doses, demonstrating hepatic cytochrome (CYP) 3A induction. Despite the high body clearance, the half-life of MDZ was in the range of 24 hours, approximately 10 times higher than after normal therapeutic doses. The volume of distribution at steady state was 33 L/kg, approximately 50 times higher than after normal therapeutic doses. The free fraction of MDZ was 58% at steady state, much higher than the 3% to 6% at normal therapeutic doses. The kinetics of intravenous MDZ is strongly dependent on its dose and on hepatic CYP3A activity. Even in patients with hepatic CYP3A induction, the half-life of MDZ increases with high doses as a result of a rise in its volume of distribution, which is a consequence of an increase in the free fraction of MDZ.