Indomethacin pharmacodynamics are altered by surfactant: a possible challenge to current indomethacin dosing guidelines created before surfactant availability.
The effect of surfactant administration for respiratory distress syndrome (RDS) on indomethacin (INDO) pharmacodynamics and dosing requirements for patent ductus arteriosus (PDA) closure and renal toxicity was evaluated. A 22-year prospective cohort study including 442 INDO-treated patients given 466 INDO treatment courses. The database included demographic information, medical problems, and medications. Neonates with a PDA confirmed by echocardiography were treated with INDO, 0.25-0.3 mg/kg. Subsequent INDO dosing was based on a combined pharmacokinetic/pharmacodynamic (PK/PD) approach. Data were fit to an Emax model and ANOVA was used to compare mean closure levels between groups. PDA closure was successful in 405 of 442 patients (91.6%) and in 434 of 466 treatment courses (93.1%) using an individualized PK/PD dosing approach. Renal toxicity was documented in 56 of 442 patients (12.7%) or 56 of 466 treatment courses (12.0%). Patients not treated with synthetic surfactant trended toward lower mean INDO concentrations at PDA closure compared to patients treated with synthetic surfactant (1.65 vs. 2.01 mg/l; P > 0.05) and significantly lower mean INDO concentrations at PDA closure compared to patients treated with natural surfactant (1.65 vs. 2.15 mg/l; P < 0.002). This requires an increased total dose of ~0.3 mg/kg or an individual dose increase of 0.1 mg/kg. Administration of natural or synthetic surfactant for RDS may increase the INDO concentrations and doses needed for PDA closure in premature infants.
McPherson
Christopher
C
Pharmacy and Newborn Medicine, St Louis Children's Hospital, St Louis, MO, USA.
Gal
Peter
P
Ransom
J Laurence
JL
Carlos
Rita Q
RQ
Dimaguila
Mary Ann V T
MA
Smith
McCrae
M
Davonzo
Christie
C
Wimmer
John E
JE
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D001682:Biological Availability; D001688:Biological Products / Q000008:administration & dosage*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004347:Drug Interactions; D004374:Ductus Arteriosus, Patent / Q000097:blood* / Q000000981:diagnostic imaging / Q000188:drug therapy*; D004452:Echocardiography; D018618:Echocardiography, Doppler, Color; D005233:Fatty Alcohols / Q000008:administration & dosage*; D019983:Guideline Adherence; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D007668:Kidney / Q000187:drug effects; D008657:Metabolic Clearance Rate; D010767:Phosphorylcholine / Q000008:administration & dosage*; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011446:Prospective Studies; D011663:Pulmonary Surfactants / Q000008:administration & dosage*; D012127:Respiratory Distress Syndrome, Newborn / Q000097:blood* / Q000000981:diagnostic imaging / Q000188:drug therapy*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001688:Biological Products; D004338:Drug Combinations; D005233:Fatty Alcohols; D011663:Pulmonary Surfactants; D010767:Phosphorylcholine; D011092:Polyethylene Glycols; C047049:dipalmitoylphosphatidylcholine, hexadecanol, tyloxapol drug combination; C117342:calfactant; C072197:beractant; D007213:Indomethacin