Pharmacokinetics of oral midazolam and 1-OH-midazolam in preterm infants

Hepatic CYP3A4 activity is low in neonates, however no data are available for intestinal CYP3A4. We determined PK of oral midazolam (M) (CYP3A4 probe) and 1-OH-M in neonates. Methods: M (0. 1 mg/kg) was administered as an oral bolus to 15 preterm infants (GA 26-31 wks, 3-13 days old). Blood samples were taken at 0, 0.5, 1, 2, 4, 6, 12 and 24 hours after M administration. M and 1OHM concentrations were determined using GC-ECD; LLD 1ng/ml (M) and 0.2 ng/ml (1OHM). PK parameters were estimated with non-compartmental analysis. Results: Cmax for M was 69.8 (47.2) ng/ml and Tmax 2.8 (3.0) h. M Cl/F was 0.24 (0.25) L/kg/h, Vss/F 3.0 (3.5) L/kg and t_1/2 7.8 (4.0) hr. In 9 patients no 1OHM could be detected. Mean 1OHM Cmax ranged from 0-22.1 ng/ml and Tmax from 0-24h. In 4 infants 1OHM PK parameters could be estimated: 1OHM t_1/2 was 4.6 (4.2) h and MRT 9.6 (6.0) h. The 1OHM/M AUC_0-24 ratio (n=15) ranged from 0-0.96. Discussion: M Cl/F is lower, M Tmax is reached later and 1OHM concentrations are much lower than in older children and adults. These data reflect in preterm infants slow 1OHM formation due to low intestinal and hepatic CYP3A levels in preterm infants.