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

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 (CL H ) and renal clearance (CL R ). The typical value of the total clearance (CL, the sum of CL R and CL H ) was 3.09 ml/h and expressed as CL/WT median = 3.96 ml/h/kg, where WT median is the median body weight. The intersubject variability of CL R and CL H were 61% and 207%, respectively. The typical value of the volume of distribution V p = 366 ml (V p /WT median = 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. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?With current weight-based dosing, indomethacin exposure is variable, and clinical response is unpredictable in preterm infants.

Pharmacokinetic and pharmacodynamic principles: unique considerations for optimal design of neonatal clinical trials

“…When using the DBS approach, hematocrit levels should be recorded in each infant, and plasma samples should also be drawn from a few infants. Hematocrit levels and matched plasma samples can be used to convert drug DBS concentrations to plasma concentrations (41,42). An advantage of collecting drug concentrations through DBS is that each pharmacokinetic samples only requires 20-30 ul of blood, making more frequent sampling feasible even with limited neonatal blood volumes.…”