Distinguishing between first-pass and systemic CYP3A-mediated metabolism of midazolam in preterm neonates using physiologically-based pharmacokinetic modelling
Janneke M. Brussee (1), Huixin Yu (1), Elke H.J. Krekels (1), Berend de Roos (1), Johannes N. van den Anker (2,3,4), Saskia N. de Wildt (2,5), Catherijne A.J. Knibbe (1,6)
(1) Division of Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands. (2) Department of Pediatric Surgery, Erasmus MC - Sophia Children’s Hospital, Rotterdam, the Netherlands. (3) Division of Paediatric Pharmacology and Pharmacometrics, University of Basel Children’s Hospital, Basel, Switzerland. (4) Division of Clinical Pharmacology, Children’s National Health System, Washington, DC. (5) Department of Pharmacology and Toxicology, Radboud University Medical Centre, Nijmegen, the Netherlands. (6) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands
Objectives: Most pharmacokinetic (PK) models do not discriminate between presystemic (intestinal and first-pass hepatic) and systemic (hepatic) CYP3A-mediated metabolism of midazolam, and can therefore not describe the presystemic formation of the primary metabolite 1-OH-midazolam. Our aim is to describe first-pass and systemic clearance of midazolam in preterm neonates using a physiologically-based PK modelling approach.
Methods: Plasma concentrations of midazolam and 1-OH-midazolam from 37 preterm neonates (postnatal age 3-46 days, body weight 0.77-2.0 kg), enrolled in a cross-over PK study, were used in this analysis [1,2]. The neonates were randomized to receive midazolam orally (n=13) or via a half-hour infusion (n=24), and an additional dose via the alternate route after >72 hours, if they still met the inclusion criteria (n=6 and n=7, respectively). A physiologically-based PK model [3,4,5] using NONMEM 7.3 was applied to describe the data, in which intrinsic clearances and distribution volumes were estimated. This model includes physiological compartments representing the gut wall, the portal vein and the liver. Tissue volumes and hepatic blood flow in preterm neonates were allometrically scaled from literature values of a term neonate [6]. The well-stirred model described hepatic clearance and the ‘Qgut’ model [7] was used to describe intestinal clearance. To describe the observed multiple peaks after a single oral or IV administration, several physiological and empirical redistribution mechanisms were tested. The model was evaluated using bootstrap and VPC.
Results: The physiologically-based PK model described midazolam and 1-OH-midazolam concentrations both and intravenous and oral doses well, except for the redistribution peaks. Intrinsic hepatic blood clearance (CLh) values were >80 times larger than intestinal blood clearance (CLg) values (4.9 L/h and 0.058 L/h respectively). Total plasma clearance was 0.195 L/h (with an estimated inter-individual variability (IIV) of 69.7%) and volume of distribution was 1.55 L (IIV 94.0%).
Conclusions: The physiological PK model could distinguish between first-pass and systemic metabolism of midazolam in preterm neonates allowing to provide additional insight in (different) maturation profiles of intestinal and hepatic CYP3A-mediated metabolism in children. The multiple peaks after a single oral or IV dose could not be described accurately by any of the evaluated redistribution models and need further research.
References:
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