Recently Registered Midazolam Doses for Preterm Neonates Do Not Lead to Equal Exposure: A Population Pharmacokinetic Model

Although midazolam is a frequently used sedative in neonatal intensive care units, its use in preterm neonates has been off-label. Recently, a new dosing advice for midazolam for sedation on intensive care units has been included in the label (0.03 mg/[kg center dot h] for preterm neonates 32 weeks). Concentration-time data of a prospective multicenter study (29 patients, median gestational age 26.7 [range 24.0-31.1 weeks]) were combined with previously published data (26 patients, median gestational age 28.1 [range 26.3-33.6 weeks]), and a population pharmacokinetic model describing the maturation of midazolam pharmacokinetics was developed in NONMEM 7.3. Clearance was 73.7 mL/h for a neonate weighing 1.1 kg and changed nonlinearly with body weight (exponent 1.69). Volume of distribution increased linearly with body weight and was 1.03 L for a neonate weighing 1.1 kg. Simulations of the newly registered dosing show considerable differences in steady-state concentrations in preterm neonates. To reach similar steady-state concentrations of 400 mu g/mL (+/- 100 mu g/mL), a dose of 0.03 mg/(kg center dot h) is adequate for neonates >= 1 kg and 2 kg and