To predict first-pass and systemic cytochrome P450 (CYP) 3A-mediated metabolism of midazolam in preterm neonates, a physiological population pharmacokinetic model was developed describing intestinal and hepatic midazolam clearance in preterm infants. On the basis of midazolam and 1-OH-midazolam concentrations from 37 preterm neonates (gestational age 26–34 weeks) receiving midazolam orally and/or via a 30-minute intravenous infusion, intrinsic clearance in the gut wall and liver were found to be very low, with lower values in the gut wall (0.0196 and 6.7 L/h, respectively). This results in a highly variable and high total oral bioavailability of 92.1% (range, 67–95%) in preterm neonates, whereas this is around 30% in adults. This approach in which intestinal and hepatic clearance were separately estimated shows that the high bioavailability in preterm neonates is explained by, likely age-related, low CYP3A activity in the liver and even lower CYP3A activity in the gut wall.

Additional Metadata
Persistent URL dx.doi.org/10.1002/psp4.12295, hdl.handle.net/1765/114008
Journal CPT: Pharmacometrics and Systems Pharmacology
Citation
Brussee, J.M, Yu, H. (Huixin), Krekels, E.H.J, de Roos, B. (Berend), Brill, M.J.E, van den Anker, J.N. (Johannes N.), … Knibbe, C.A.J. (2018). First-Pass CYP3A-Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates. CPT: Pharmacometrics and Systems Pharmacology, 7(6), 374–383. doi:10.1002/psp4.12295