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

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)1.54; V (L)=0.484 (WT / 0.936)1.41; F=0.986; Ka (h(-1))=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.

journal_name

Ther Drug Monit

authors

Al Za'abi M,Donovan T,Tudehope D,Woodgate P,Collie LA,Charles B

doi

10.1097/FTD.0b013e31815b3e13

subject

Has Abstract

pub_date

2007-12-01 00:00:00

pages

807-14

issue

6

eissn

0163-4356

issn

1536-3694

pii

00007691-200712000-00014

journal_volume

29

pub_type

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