P Burtin (1,3), E Jacqz-Aigrain (1), P Girard (2)
(1)Unité de Pharmacologie Clinique, Hopital Robert Debré, Paris, France; (2)Unité de Pharmacologie Clinique, Hopital Neuro-Cardiologique, Lyon, France; (3)Currently in post-doctoral stay at Sandoz Pharma, Drug Safety/Pharmacometrics, Basel, Switzerland.
Midazolam, a watersoluble benzodiazepine with a short half-life, has been used in neonatal intensive care units for several years using dosage regimens empirically derived from pediatric studies. The population pharmacokinetics of midazolam was studied in 187 neonates requiring intravenous sedation for artificial ventilation.
The 531 concentration measurements obtained were analysed using NONMEM and a 2-compartment model with four parameters : clearance (Cl), central volume (Vc), peripheral volume (Vp), and intercompartmental clearance (Q). The influence of birth weight (range 700 to 5200 g), gestational age (range 26 to 42 weeks), postnatal age (range 0 to 10 days), and co-medications were investigated.
Cl and Vc (mean +/- SE) were found to be directly proportional to birth weight (Cl= 0.070 + /- 0.013 l/kg/h, Vc= 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 sympathomimetic amines. The post-natal age had no apparent effect on midazolam kinetics. The Vp and Q (mean +/- SE) (0.42 +/-0.11 I and 0.29 +/- 0.08 l/h, respectively) were not influenced by any of the covariates studied. There was a large interindividual variability for the pharmacokinetic parameters.
The mean midazolam doses required for critically ill neonates are lower than those required for older infants. The large interindividual variability would justify the use of therapeutic drug monitoring.
Reference: PAGE 3 (1994) Abstr 853 [www.page-meeting.org/?abstract=853]
Poster: poster