Population Pharmacokinetics of Unbound Hydrocortisone in Critically Ill Neonates and Infants With Vasopressor-Resistant Hypotension

Abstract

Objective To determine the population pharmacokinetics of unbound hydrocortisone (HC) in critically ill neonates and infants receiving intravenous HC for treatment of vasopressor-resistant hypotension and to identify patient-specific sources of pharmacokinetic variability. Design Prospective observational cohort study. Setting Level 3 neonatal intensive care unit. Patients Sixty-two critically ill neonates and infants receiving intravenous HC as part of standard of care for the treatment of vasopressor-resistant hypotension: median gestational age 28 weeks (range, 23 to 41), median weight 1.2 kg (range, 0.5 to 4.4), 29 females. Interventions None. Measurements Unbound baseline cortisol and post-dose HC concentrations measured from blood samples being drawn for routine laboratory tests. Main Results A one compartment model best described the data. Allometric weight and postmenstrual age (PMA) were significant covariates on unbound HC clearance (CL) and volume of distribution (V). Final population estimates for CL, V, and baseline cortisol concentration were 20.2 L/h, 244 L, and 1.37 ng/mL, respectively. Using the median weight and PMA of our subjects (i.e. 1.2 kg and 28 weeks) in the final model, the typical unbound HC CL and V were 1.0 L/h and 4.2 L, respectively. The typical half-life for unbound HC was 2.9 hours. A sharp and continuous increase in unbound HC CL was observed at 35 weeks PMA. Conclusions We report the first pharmacokinetic data for unbound HC, the pharmacologically active moiety, in critically ill neonates and infants with vasopressor-resistant hypotension. Unbound HC CL increased with body weight and was faster in children with an older PMA. Unbound HC CL increased sharply at 35 weeks PMA and continued to mature thereafter. This study lays the groundwork for evaluating unbound HC exposure-response relationships and drawing definitive conclusions about the dosing of intravenous HC in critically-ill neonates and infants with vasopressor-resistant hypotension.

Analysis of microsamples by miniaturized magnetic-based pipette tip microextraction: determination of free cortisol in serum and urine from very low birth weight preterm newborns

“…Additionally, the levels of urinary free cortisol were also measured in the same children, obtaining similar values between them. Our results are in agreement with previous studies in sick preterm infants 22 which found population reference values of 1.37 ng mL −1 . Urinary free cortisol levels were also in the normal range for newborn children.…”

“…21 According to previous literature, one of the few studies available that measured free cortisol in sick preterm infants found a reference value of 1.37 ng mL −1 for this population. 22 On the other hand, the analysis of urinary free cortisol (UFC) may be a good biomarker for the diagnosis of Cushing's syndrome. 23 These analyses have been commonly performed by means of immunoassays.…”

Clinical Pharmacology of hydrocortisone in infants and children

“…The metabolism of hydrocortisone has been studied in human liver microsomes and the metabolites generated are cortisone, dihydrocortisol, dihydrocortisone, and 6β-hydroxycortisol [14]. Vezina, et al [15] studied the pharmacokinetics of hydrocortisone in 62 newborns and infants, the total body clearance of hydrocortisone is 20.2 L/h, and the 95% coefficient interval is 15.9 and 24.5 L/h indicating that the total body clearance varies among the newborns and infants [15]. Michelet, et al [16] studied the pharmacokinetics of hydrocortisone in 12 children, 6 infants, and 6 newborns, the total body clearance of hydrocortisone is 400 L/h, and the 95% coefficient interval is 353 and 468 L/h indicating that the total body clearance of hydrocortisone varies in children, infants, and newborns [16].…”

“…Vezina, et al [15] studied the pharmacokinetics of hydrocortisone in 62 newborns and infants with median postmenstrual age, postnatal age, and body-weight of 27 weeks (range, 23 to 41), 0.7 weeks (range, 0.1 to 9.3), and 1.2 kg (range, 0.5 to 4.4). Thirty-three (53.2%) subjects were males and 29 (46.8%) were females and hydrocortisone was intravenously infused at a dose of 45 mg/m 2 daily divided in 4 doses.…”

Paediatric population pharmacokinetic modelling to assess hydrocortisone replacement dosing regimens in young children

“…Currently, there is limited data on hydrocortisone replacement levels in young paediatric patients (<6 years of age) (21,22) and no paediatric pharmacokinetic model for hydrocortisone in this age range. Other pharmacokinetic data available have been undertaken in either adults or children over the age of 5 years (23,24,25,26,27,28).…”