Orogastric and intravenous indomethacin administration to very premature neonates with patent ductus arteriosus: Population pharmacokinetics, absolute bioavailability, and treatment outcome

Mohammed Al Za'abi, Timothy Donovan, David Tudehope, Paul Woodgate, Li An Collie, Bruce Charles

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Abstract

A population pharmacokinetic model was developed after administration of orogastric and/or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants. Plasma indomethacin concentrations (n = 227) were obtained from 90 preterm infants of median gestational age 27 weeks, mean postnatal age of 12 days, and a mean current weight (WT) of 1010 g. Infants received one to three courses of indomethacin (0.1 mg/kg per day for 6 days). A one-compartment model was fitted to the data to obtain estimates of clearance (CL), volume of distribution (V), absorption rate constant (Ka) and orogastric bioavailability (F), using NONMEM. Model robustness was assessed by bootstrapping with replacement (500 samples). The structural model was: CL (L/h) = 0.0166 (WT ÷ 0.936); V (L) = 0.484 (WT ÷ 0.936); F = 0.986; Ka (h) = 0.786. The interindividual variability for CL and V was 57.7% and 45.6%, respectively. There remained considerable residual unexplained variability (45.4%). Mean (range) conditional estimates from individual infants for CL, V, and elimination half-life were 18.9 (4.7-45.5) mL/h/kg, 509 (191-1120) mL/kg, and 20.0 (12.0-37.3) hours, respectively. Complete ductus closure occurred in 67% of patients. Infants of lower gestational age or birth weight had less chance of successful ductal closure. There was no obvious dose-response relationship between systemic exposure to varying plasma indomethacin concentrations and ductus closure, which does not support individualized indomethacin dosing based on monitoring to a target plasma concentration.

Original languageEnglish
Pages (from-to)807-814
Number of pages8
JournalTherapeutic Drug Monitoring
Volume29
Issue number6
DOIs
Publication statusPublished - Dec 2007

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Keywords

  • Ductus arteriosus
  • Indomethacin
  • Population pharmacokinetics
  • Preterm infants
  • Therapeutic drug monitoring

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis
  • Pharmacology
  • Biochemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology (medical)
  • Public Health, Environmental and Occupational Health

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