Developmental pharmacokinetics of indomethacin in preterm neonates: Severely decreased drug clearance in the first week of life.

Creator(s)

Wojciech Krzyzanski
Bradley Stockard, Children's Mercy Kansas City
Andrea Gaedigk, Children's Mercy Kansas CityFollow
Allison Scott, Children's Mercy HospitalFollow
Whitney M. Nolte, Children's Mercy HospitalFollow
Kim T. Gibson, Children's Mercy HospitalFollow
J Steven Leeder, Children's Mercy HospitalFollow
Tamorah Lewis

Document Type

Article

Publication Date

1-2023

Identifier

DOI: 10.1002/psp4.12881; PMCID: PMC9835126

Abstract

Indomethacin is used commonly in preterm neonates for the prevention of intracranial hemorrhage and closure of an abnormally open cardiac vessel. Due to biomedical advances, the infants who receive this drug in the neonatal intensive care unit setting have become younger, smaller, and less mature (more preterm) at the time of treatment. To develop a pharmacokinetics (PK) model to aid future dosing, we designed a prospective cohort study to characterize indomethacin PK in a dynamically changing patient population. A population PK base model was created using NONMEM, and a covariate model was developed in a primary development cohort and subsequently was tested for accuracy in a validation cohort. Postnatal age was a significant covariate for hepatic clearance (CLH ) and renal clearance (CLR ). The typical value of the total clearance (CL, the sum of CLR and CLH ) was 3.09 ml/h and expressed as CL/WTmedian = 3.96 ml/h/kg, where WTmedian is the median body weight. The intersubject variability of CLR and CLH were 61% and 207%, respectively. The typical value of the volume of distribution Vp = 366 ml (Vp /WTmedian = 470 ml/kg), and its intersubject variability was 38.8%. Half-life was 82.1 h. Compared with more mature and older preterm populations studied previously, indomethacin CL is considerably lower in this contemporary population. Model-informed precision dosing incorporating important covariates other than weight alone offers an opportunity to individualize dosing in a susceptible patient undergoing rapid change.

Journal Title

CPT Pharmacometrics Syst Pharmacol

Volume

12

Issue

1

First Page

110

Last Page

121

MeSH Keywords

Infant, Newborn; Infant; Humans; Indomethacin; Infant, Premature; Prospective Studies; Drug Elimination Routes; Forecasting

Keywords

Indomethacin; Prospective Studies; Drug Elimination Routes; Forecasting

Comments

Grant support

• 76230/Robert Wood Johnson Foundation
• 5K23HD091362/NH/NIH HHS/United States
• T32 HD069038/NH/NIH HHS/United States
• 5K23HD091362/NH/NIH HHS/United States
• T32 HD069038/NH/NIH HHS/United States

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Publisher's Link: https://ascpt.onlinelibrary.wiley.com/doi/10.1002/psp4.12881

Recommended Citation

Krzyzanski W, Stockard B, Gaedigk A, et al. Developmental pharmacokinetics of indomethacin in preterm neonates: Severely decreased drug clearance in the first week of life. CPT Pharmacometrics Syst Pharmacol. 2023;12(1):110-121. doi:10.1002/psp4.12881