Population pharmacokinetic modeling in very premature infants receiving midazolam during mechanical ventilation - Midazolam neonatal pharmacokinetics

Background: Midazolam is used widely as a sedative to facilitate mechanical ventilation. This prospective study investigated the population pharmacoki netics of midazolam in very premature infants. Methods: Midazolam (100 mu g/hg) was administered as a rapid intravenous bo lus dose every 4-6 h to 60 very premature neonates with a mean (range) gest ational age of 27 weeks (24-31 weeks), a birth weight of 965 g (523-1,470 g ), and an age of 4.5 days (2-15 days). A median (range) of four tone to fou r) blood samples, 0.2 ml each, were drawn at random times after the first d ose or during continuous treatment, and concentrations of midazolam in seru m were assayed by high-performance liquid chromatography. A population anal ysis was conducted using a two-compartment pharmacokinetic model using the NONMEM program. Results: Average parameter values (interpatient percent coefficient of vari ation) for infants with birth weights 1,000 g or less were total systemic c learance (Cl-T) = 0.783 ml/min (83%), intercompartmental clearance (Cl-Q) = 6.53 ml/min (116%), volume of distribution of the central compartment (V-1 ) = 473 ml (70%), and volume of distribution of the peripheral compartment (V-2) = 513 ml (146%). For infants with birth weights more than 1,000 g the y were as follows: Cl-T = 1.24 ml/min (78%), Cl-Q = 9.82 ml/min (98%), V-1 = 823 ml (43%), and V-2 = 1,040 ml (193%). The intrapatient variability (pe rcent coefficient of variation) in the data was 4.5% at the mean concentrat ion midazolam in serum of 121 ng/ml. Conclusions: Serum concentration-time data were used in modeling the popula tion pharmacokinetics of midazolam in very premature, ventilated neonates. Clearance of midazolam was markedly decreased compared with previous data f rom term infants and older patients. Infants weighing less than 1,000 g at birth had significantly lower clearance than those weighing more than 1,000 g.