title: Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants.
abstract: Preterm infants with respiratory distress syndrome (RDS) given inositol had reduced bronchopulmonary dysplasia (BPD), death and severe retinopathy of prematurity (ROP). We assessed the safety and pharmacokinetics of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization.
  
  
  
  Infants ≤ 29 wk GA (n = 122, 14 centers) were randomized and treated with placebo or inositol at 10, 40, or 80 mg/kg/d. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 wk, 34 wk postmenstrual age (PMA) or discharge. Serum collection employed a sparse sampling population pharmacokinetics design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored.
  
  
  
  At 80 mg/kg/d mean serum levels reached 140 mg/l, similar to Hallman's findings. Levels declined after 2 wk, converging in all groups by 6 wk. Analyses showed a mean volume of distribution 0.657 l/kg, clearance 0.058 l/kg/h, and half-life 7.90 h. Adverse events and comorbidities were fewer in the inositol groups, but not significantly so.
  
  
  
  Multiple dose inositol at 80 mg/kg/d was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a phase III trial.
authors.affiliation: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York.
authors.forename: Dale L
authors.identifier: 0000-0002-7878-5325
authors.initials: DL
authors.lastname: Phelps
authors.affiliation: Department of Pediatrics, and Pediatric Pharmacology, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Ward
authors.affiliation: Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina.
authors.forename: Rick L
authors.initials: RL
authors.lastname: Williams
authors.affiliation: Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Nolen
authors.affiliation: Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Watterberg
authors.affiliation: Department of Pediatrics, Women & Infants' Hospital Brown University, Providence, Rhode Island.
authors.forename: William
authors.initials: W
authors.lastname: Oh
authors.affiliation: Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina.
authors.forename: Michael
authors.initials: M
authors.lastname: Goedecke
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Ehrenkranz
authors.affiliation: Pharmacology and Toxicology Division, RTI International, Research Triangle Park, North Carolina.
authors.forename: Timothy
authors.initials: T
authors.lastname: Fennell
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Brenda B
authors.initials: BB
authors.lastname: Poindexter
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Cotten
authors.affiliation: PEDEGO Research Center, and MRC Oulu, and Oulu University Hospital, Oulu, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Hallman
authors.affiliation: Department of Pediatrics, Floating Hospital for Children, Tufts Medical Center, Boston, Massachusetts.
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Frantz
authors.affiliation: Department of Pediatrics, and Pediatric Pharmacology, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Roger G
authors.initials: RG
authors.lastname: Faix
authors.affiliation: Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Zaterka-Baxter
authors.affiliation: Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, Maryland.
authors.forename: Abhik
authors.initials: A
authors.lastname: Das
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, California.
authors.forename: M Bethany
authors.initials: MB
authors.lastname: Ball
authors.affiliation: Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
authors.forename: Conra Backstrom
authors.initials: CB
authors.lastname: Lacy
authors.affiliation: Department of Pediatrics, Rainbow Babies & Children's Hospital, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Michele C
authors.initials: MC
authors.lastname: Walsh
authors.affiliation: Department of Pediatrics, Division of Neonatology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Waldemar A
authors.initials: WA
authors.lastname: Carlo
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Sánchez
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, Iowa.
authors.forename: Edward F
authors.initials: EF
authors.lastname: Bell
authors.affiliation: Department of Pediatrics, Wayne State University, Detroit, Michigan.
authors.forename: Seetha
authors.initials: S
authors.lastname: Shankaran
authors.affiliation: Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia.
authors.forename: David P
authors.initials: DP
authors.lastname: Carlton
authors.affiliation: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York.
authors.forename: Patricia R
authors.initials: PR
authors.lastname: Chess
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: Rosemary D
authors.initials: RD
authors.lastname: Higgins
mesh_terms: D001997:Bronchopulmonary Dysplasia / Q000150:complications; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D007262:Infusions, Intravenous; D007294:Inositol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D061214:Patient Safety; D012127:Respiratory Distress Syndrome, Newborn / Q000150:complications / Q000188:drug therapy*; D012178:Retinopathy of Prematurity / Q000150:complications; D013997:Time Factors
chemical_list: D007294:Inositol