The single-dose pharmacokinetics of midazolam and its primary metabolite in pediatric patients after oral and intravenous administration

The first-dose pharmacokinetics of midazolam and its primary alpha -hydroxy metabolite were studied after single-dose administration. Eligible study p atients were enrolled into one of three study arms: Arm I (midazolam/metabo lite pharmacokinetic evaluation after oral administration of a syrup formul ation), Arm II (the absolute bioavailability of midazolam syrup), and Arm I II (midazolam and metabolite pharmacokinetics after IV administration). Com plete blood sampling for pharmacokinetic analysis was available in 87 subje cts. Midazolam absorption after administration. of the oral syrup formulati on was rapid, with adolescents absorbing the drug at approximately half the rate observed in younger children (ages 2 to < 12 years). Furthermore, mid azolam t(1/2) was prolonged and CL/F reduced in adolescents as compared wit h younger children. Although the midazolam V-d/F appeared larger in the you ngest age group after oral administration, this observation was not apparen t after IV dosing, suggesting subject differences in bioavailability rather than distribution. Like midazolam, the disposition characteristics for alp ha -hydroxymidazolam were also highly variable, with the greatest formation of metabolite (reflected by the AUC ratio) observed in children ages 2 to < 12 years. The AUC ratios of alpha -hydroxymidazolam to midazolom after IV dosing were similar across all age groups and were smaller than correspond ing values following oral administration. The absolute bioavailability of m idazolam averaged 36% with a very broad range (9%-71%). No relationship bet ween midazolam bioavailability and age was observed. Overall, the dispositi on characteristics of midazolam and its alpha -hydroxy metabolite were high ly variable, appeared independent of age and dose administered, and were li near over the dose range studied (0.25 to 1 mg/kg). These data suggest that an initial oral dose of 0.2 to 0.3 mg/kg should be adequate for successful sedation of most pediatric patients. The inherent variability in midazolom bioavailability and metabolism underscores the importance of titrating mid azolam dose to desired effect. (C) 2001 the American College of Clinical Ph armacology.