Indomethacin exposure increases midazolam clearance in preterm infants

We determined the effect of clinical parameters and indomethacin on PK of IV medazolam (M) and 1-OH-midazolam (1OHM) in neonates. Methods: M (0.1 mg/kg) was administered to 24 preterm infants (GA 26-34 wks, 3-13 days old) as a 30 minute infusion. 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 GCECD; LLD Ing/ml (M) and 0.2 ng/ml (1OHM). PK parameters were estimated using non-compartmental methods. Associations between clinical parameters/co-medication and M PK were analyzed with Spearman's correlation and multivariate analysis. Results: Both postnatal age and indomethacin administration (for PDA) showed a significant relationship with M Cl (L/h/kg). Multiple regression showed that M Cl was increased after indomethacin treatment (p=0.01), while, adjusted for this effect, there was no predictive value for postnatal age (p=0.77). Discussion: The indomethacin-related increase of M Cl shows that renal and/or hemodynamic factors may be important determinants M PK in preterm infants in addition to hepatic metabolism.