POPULATION PHARMACOKINETICS OF MIDAZOLAM IN NEONATES

Objective: To describe the pharmacokinetics of midazolam, a water-soluble benzodiazepine with a shea half-life, in critically ill neonates. Hypothesis: Midazolam clearance is reduced in neonates compared with clearance in children, and the doses currently in use, which are derived from pediatric studies, are excessive. Patients and Methods: This population study was conducted in 187 neonates requiring intravenous sedation for artificial ventilation, The 531 midazolam concentration measurements obtained were analyzed by use of NONMEM and a two-compartment model with four parameters: clearance (CL), central volume (V-c), peripheral volume (V-p), and intercompartmental clearance (Q), The influence of birth weight (range, 700 to 5200 gm), gestational age (range, 26 to 42 weeks), postnatal age (range, 0 to 10 days), and comedications were investigated. Results: CL and V-c (mean +/- SE) were found to be directly proportional to birth weight (CL 0.070 +/- 0.013 L/kg/hr; V-c = 0.591 +/- 0.065 L/kg), The CL was 1.6 times higher in neonates with a gestational age of more than 39 weeks, It was 0.7 times lower in neonates receiving inotropic support, The postnatal age had no apparent effect on midazolam kinetics. The V-p and Q (mean +/- SE; 0.42 +/- 0,11 L and 0.29 +/- 0.08 L/hr, respectively) were not influenced by any of the covariates studied. There was a large interindividual variability for the pharmacokinetic parameters. Conclusion: The mean midazolam doses required for critically ill neonates are lower than those required for older infants.