Indomethacin Pharmacodynamics Are Altered by Surfactant: A Possible Challenge to Current Indomethacin Dosing Guidelines Created Before Surfactant Availability

• Published in: Pediatric cardiology 2010-05, Vol.31 (4), p.505-510
• Main Authors: McPherson, Christopher, Gal, Peter, Ransom, J. Laurence, Carlos, Rita Q., Dimaguila, Mary Ann V. T., Smith, McCrae, Davonzo, Christie, Wimmer, John E.
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Anti-Inflammatory Agents, Non-Steroidal - toxicity; Biological Availability; Biological Products - administration & dosage; Calfactant; Cardiac Surgery; Cardiology; Care and treatment; Cohort Studies; Congenital heart disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Interactions; Ductus Arteriosus, Patent - blood; Ductus Arteriosus, Patent - diagnostic imaging; Ductus Arteriosus, Patent - drug therapy; Echocardiography; Echocardiography, Doppler, Color; Fatty Alcohols - administration & dosage; Guideline Adherence; Humans; Indomethacin; Indomethacin - administration & dosage; Indomethacin - pharmacokinetics; Indomethacin - toxicity; Infant, Newborn; Intensive Care Units, Neonatal; Kidney - drug effects; Medical research; Medicine; Medicine & Public Health; Medicine, Experimental; Metabolic Clearance Rate; Neonatology; Original Article; Phosphorylcholine - administration & dosage; Polyethylene Glycols - administration & dosage; Prospective Studies; Pulmonary Surfactants - administration & dosage; Respiratory Distress Syndrome, Newborn - blood; Respiratory Distress Syndrome, Newborn - diagnostic imaging; Respiratory Distress Syndrome, Newborn - drug therapy; Vascular Surgery
• ISSN: 0172-0643; 1432-1971
• DOI: 10.1007/s00246-009-9628-6

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