title: 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.
authors.affiliation: Pharmacy and Newborn Medicine, St Louis Children's Hospital, St Louis, MO, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: McPherson
authors.forename: Peter
authors.initials: P
authors.lastname: Gal
authors.forename: J Laurence
authors.initials: JL
authors.lastname: Ransom
authors.forename: Rita Q
authors.initials: RQ
authors.lastname: Carlos
authors.forename: Mary Ann V T
authors.initials: MA
authors.lastname: Dimaguila
authors.forename: McCrae
authors.initials: M
authors.lastname: Smith
authors.forename: Christie
authors.initials: C
authors.lastname: Davonzo
authors.forename: John E
authors.initials: JE
authors.lastname: Wimmer
mesh_terms: 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*
chemical_list: 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