Janneke M. Brussee (1), Saskia N. de Wildt (2), Meindert Danhof (1), Catherijne A.J. Knibbe (1,2,3)
(1) Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands, (2) Erasmus MC Sophia Children’s Hospital, Rotterdam, the Netherlands, (3) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands
Objectives: Midazolam is a benzodiazepine which is often used for sedation in neonatal and pediatric intensive care units orally or intravenously. For sedation of preterm neonates, the use of midazolam is largely off-label. This project aims to describe and predict CYP3A mediated clearance and oral bioavailability of midazolam in preterm neonates using data from a cross-over study on oral and intravenous midazolam.
Methods: Patients included 38 preterm neonates (postnatal age ranging between 3-46 days, birth weight 745-2135 grams) from the neonatal intensive care unit of the Sophia’s Children Hospital in Rotterdam [1,2]. They were randomly assigned to receive midazolam orally (n=13) or via an half-hour infusion (n=25), and they received midazolam via the alternate route after >72 hours, if they still met the inclusion criteria (n=13). A sequential drug-metabolite population pharmacokinetic model for midazolam and its primary metabolite, 1-OH-midazolam, was developed using NONMEM 7.3. CYP3A mediated formation clearance of 1-OH-midazolam was assumed to be a fraction of 60% of total midazolam clearance [3,4]. Birth weight, body weight during the study, postnatal age and gestational age were considered as potential covariates. A non-parametric bootstrap was performed to evaluate the model.
Results: A two-compartmental PK model with values for clearance and central volume of distribution of 0.135 L/h and 0.542 L, respectively, was used to describe the plasma concentrations of midazolam. Oral absorption was best described by a first-order process with an absorption rate of 2.05 hr(-1) and bioavailability of 0.72. Plasma concentrations of 1-OH-midazolam were described by a 1-compartment model with an estimated clearance of 0.48 L/h and a volume of distribution equalized to the volume of distribution of midazolam. No significant covariates were found, likely because the studied population was very uniform.
Conclusions: Based on data from a cross-over study on oral and intravenous midazolam, a pharmacokinetic model for midazolam and metabolites was identified for preterm neonates. Compared to adults, clearance of midazolam seems lower and bioavailability higher. In the combined oral and intravenous model, there was no evidence for pre-systemic formation of the CYP3A mediated metabolite (1-OH-midazolam) [5] after oral administration in preterm neonates.
References:
[1] De Wildt SN et al, Br J Clin Pharmacol. 2002 Apr;53(4):390-2
[2] De Wildt SN et al, Clin Pharmacol Ther. 2001 Dec;70(6):525-31
[3] Peeters MY et al, Anesthesiology. 2006 Dec;105(6):1135-46
[4] Heizmann P, Ziegler WH, Arzneimittelforschung. 1981;31(12a):2220-3
[5] Frechen S et al, Clin Pharmacokinet. 2013 Sep;52(9):763-81
Reference: PAGE 24 () Abstr 3564 [www.page-meeting.org/?abstract=3564]
Poster: Drug/Disease modeling - Paediatrics