Effect of age and birth weight on indomethacin pharmacodynamics in neonates treated for patent ductus arteriosus.
OBJECTIVE
To determine patent ductus arteriosus (PDA) closure rates, and indomethacin (INDO) toxicity rates in neonates dosed with INDO using an individualized pharmacokinetic/pharmacodynamic (PK/PD) dosing approach. In addition, develop PD curves evaluating dose-response and concentration-response relationships for closure and renal toxicity, especially in select subgroups historically known as "poor responders" (<1000 g and > or = 10 days postnatal age).


METHODS
Prospective, cohort study.


METHODS
Level III neonatal intensive care unit.


METHODS
One hundred thirty-nine patients receiving 151 courses of INDO for PDA closure were evaluated.


METHODS
Patients initially received 0.25 mg/kg of INDO, followed immediately by 1 mg/kg of furosemide. INDO concentrations were obtained 2 hrs and 8 hrs after the dose and were assayed using high-performance liquid chromatography. Individualized PK parameters were calculated with subsequent INDO dosing based on the individualized PK variables to increase trough serum concentrations by 0.3-0.5 mg/L.


RESULTS
Ductal closure was successful in 127 patients (91%). Renal toxicity occurred in 21 (15%) patients and was temporary and reversible. No significant differences in response rates based on treatment weight or postnatal age were observed. PD curves were similar for neonates <1000 g vs. > or = 1000 g. PD curves were also similar for neonates with postnatal age <10 days vs. > or = 10 days. Statistically significant differences were noted between neonates categorized for postnatal age <10 days vs. > or = 10 days in total days of therapy (1.8 vs. 2.3 days), total number of doses required to close PDA (3.5 vs. 5.6 doses), critical INDO dose (0.9 vs. 1.4 mg/kg), critical INDO concentration (1.9 vs. 1.4 mg/L), and critical dose/critical concentration ratio (0.52 vs. 2.2).


CONCLUSIONS
These findings support the hypothesis that the poor PDA closure rates with INDO for neonates >10 days postnatal age are the result of pharmacokinetic differences only and that weight does not impact response rates. Individualized pharmacokinetic/pharmacodynamic dosing of INDO continues to achieve higher closure rate than current dosing standards. Patients historically known as poor responders significantly benefit from this dosing approach.
Shaffer
Christopher L
CL
Greensboro Area Health Eduction Center and the Department of Neonatal Medicine, Women's Hospital of Greensboro, University of North Carolina at Chapel Hill, Greenboro, NC, USA.
Gal
Peter
P
Ransom
J Laurence
JL
Carlos
Rita Q
RQ
Smith
McCrae S
MS
Davey
Andrew M
AM
Dimaguila
Mary Ann V T
MA
Brown
Yvonne L
YL
Schall
Stewart A
SA
D000367:Age Factors; D000465:Algorithms; D001724:Birth Weight; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004374:Ductus Arteriosus, Patent / Q000188:drug therapy*; D005865:Gestational Age; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007231:Infant, Newborn; D011446:Prospective Studies; D012016:Reference Values; D016896:Treatment Outcome
D002317:Cardiovascular Agents; D007213:Indomethacin