TY - JOUR
T1 - Orogastric and intravenous indomethacin administration to very premature neonates with patent ductus arteriosus
T2 - Population pharmacokinetics, absolute bioavailability, and treatment outcome
AU - Za'abi, Mohammed Al
AU - Donovan, Timothy
AU - Tudehope, David
AU - Woodgate, Paul
AU - Collie, Li An
AU - Charles, Bruce
PY - 2007/12
Y1 - 2007/12
N2 - 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.
AB - 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.
KW - Ductus arteriosus
KW - Indomethacin
KW - Population pharmacokinetics
KW - Preterm infants
KW - Therapeutic drug monitoring
UR - http://www.scopus.com/inward/record.url?scp=36549078271&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=36549078271&partnerID=8YFLogxK
U2 - 10.1097/FTD.0b013e31815b3e13
DO - 10.1097/FTD.0b013e31815b3e13
M3 - Article
C2 - 18043480
AN - SCOPUS:36549078271
SN - 0163-4356
VL - 29
SP - 807
EP - 814
JO - Therapeutic Drug Monitoring
JF - Therapeutic Drug Monitoring
IS - 6
ER -