Intravenous indometacin in preterm infants with symptomatic patent ductus arteriosus. A population pharmacokinetic study

• Published in: British journal of clinical pharmacology Vol. 58; no. 3; pp. 249 - 258
• Main Authors: Smyth, J. M., Collier, P. S., Darwish, M., Millership, J. S., Halliday, H. L., Petersen, S., McElnay, J. C.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-09-2004; Blackwell Science; Blackwell Science Inc
• Subjects: Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cardiovascular Agents - administration & dosage; Cardiovascular Agents - pharmacokinetics; Ductus Arteriosus, Patent - drug therapy; Female; Humans; indometacin; Indomethacin - administration & dosage; Indomethacin - pharmacokinetics; Infant; Infant, Newborn; Infant, Premature; Infusions, Intravenous; Male; Medical sciences; patent ductus arteriosus; Pharmacokinetics; Pharmacology. Drug treatments; population pharmacokinetics; preterm infants; Human; Premature; population pharacokinetics; Prostaglandin-endoperoxide synthase; Intravenous administration; Enzyme; preterm infants; Indometacin; Enzyme inhibitor; Infant; Ductus arteriosus; Tocolytic; Non steroidal antiinflammatory agent; Indoleacetic acid derivatives; patent ductus arteriosus; Oxidoreductases; Pharmacokinetics
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2004.02139.x

Aims
To characterize the population pharmacokinetics of indometacin in preterm infants with symptomatic patent ductus arteriosus and to investigate the influence of various factors on the response to treatment.
Methods
Data were collected from 35 infants (gestational age 25–34 weeks; postnatal age 1–77 days) in neonatal units in Belfast and Copenhagen. Infants received an initial course of up to three doses of intravenous indometacin (0.1–0.2 mg kg−1) as considered appropriate by the treating physician. For those infants who did not respond to therapy or in whom the ductus reopened, a second course was sometimes given. Population analysis of the 185 plasma concentrations obtained was conducted using NONMEM and pharmacokinetic and demographic differences between responders and nonresponders were compared.
Results
The concentration‐time course of indometacin was best described by a one‐compartment model. The final population parameter estimates of clearance (CL) and volume of distribution (V) (standardized to the median weight of 1.17 kg) were 0.00711 l h−1 and 0.266 l, respectively. CL increased from birth by approximately 3.38% per day and V by approximately 1.47% per day. Concomitant digoxin therapy resulted in a 30% decrease in V. Interindividual variability in CL and V was 41% and 21%, respectively. Interoccasion variability for CL was 43%. Residual variability corresponded to a standard deviation of 0.148 mg l−1. Closure occurred in 75% of infants with a plasma concentration ≥ 0.4 mg l−1 24 h after the last dose.
Conclusions
Dosing regimens for indometacin should take into account the weight and postnatal age of the infant and any concomitant digoxin therapy. The population estimates can be used to determine typical values of CL and V allowing the prediction of individualized doses of indometacin that should increase the probability of achieving a 24 h plasma concentration ≥ 0.4 mg l−1. Although the pharmacokinetic estimates will be affected by both interindividual and within‐individual variation, it is anticipated that this approach will decrease the variability of exposure and optimize treatment outcome.