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Indomethacin pharmacodynamics are altered by surfactant: a possible challenge to current indomethacin dosing guidelines created before surfactant availability.

Abstract

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.

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  • Publisher Full Text
  • Authors

    McPherson C, Gal P, Ransom JL, Carlos RQ, Dimaguila MA, Smith M, Davonzo C, Wimmer JE

    Institution

    Pharmacy and Newborn Medicine, St Louis Children's Hospital, St Louis, MO, USA.

    Source

    Pediatric cardiology 31:4 2010 May pg 505-10

    MeSH

    Animals
    Anti-Inflammatory Agents, Non-Steroidal
    Biological Availability
    Biological Products
    Cohort Studies
    Dose-Response Relationship, Drug
    Drug Administration Schedule
    Drug Combinations
    Drug Interactions
    Ductus Arteriosus, Patent
    Echocardiography
    Echocardiography, Doppler, Color
    Fatty Alcohols
    Guideline Adherence
    Humans
    Indomethacin
    Infant, Newborn
    Intensive Care Units, Neonatal
    Kidney
    Metabolic Clearance Rate
    Phosphorylcholine
    Polyethylene Glycols
    Prospective Studies
    Pulmonary Surfactants
    Respiratory Distress Syndrome, Newborn

    Pub Type(s)

    Comparative Study
    Journal Article

    Language

    eng

    PubMed ID

    20063159