Pharmacokinetics and safety of a single intravenous dose of myo-inositol in preterm infants of 23-29 wk.
BACKGROUND
Myo-inositol given to preterm infants with respiratory distress has reduced death, increased survival without bronchopulmonary dysplasia, and reduced severe retinopathy of prematurity in two randomized trials. Pharmacokinetic (PK) studies in extremely preterm infants are needed before efficacy trials.


METHODS
Infants born in 23-29 wk of gestation were randomized to a single intravenous (i.v.) dose of inositol at 60 or 120 mg/kg or placebo. Over 96 h, serum levels (sparse sampling population PK) and urine inositol excretion were determined. Population PK models were fit using a nonlinear mixed-effects approach. Safety outcomes were recorded.


RESULTS
A single-compartment model that included factors for endogenous inositol production, allometric size based on weight, gestational age strata, and creatinine clearance fit the data best. The central volume of distribution was 0.5115 l/kg, the clearance was 0.0679 l/kg/h, endogenous production was 2.67 mg/kg/h, and the half-life was 5.22 h when modeled without the covariates. During the first 12 h, renal inositol excretion quadrupled in the 120 mg/kg group, returning to near-baseline value after 48 h. There was no diuretic side effect. No significant differences in adverse events occurred among the three groups (P > 0.05).


CONCLUSIONS
A single-compartment model accounting for endogenous production satisfactorily described the PK of i.v. inositol.
The School of Medicine and Dentistry, University of Rochester, Rochester, New York.
Dale L
DL
Phelps
Department of Pediatrics, Division of Neonatology, School of Medicine, University of Utah, Salt Lake City, Utah.
Robert M
RM
Ward
Statistics and Epidemiology Unit, RTI International, Research Triangle Park, North Carolina.
Rick L
RL
Williams
University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
Kristi L
KL
Watterberg
Department of Pediatrics, Women and Infants Hospital, Brown University, Providence, Rhode Island.
Abbot R
AR
Laptook
Statistics and Epidemiology Unit, RTI International, Research Triangle Park, North Carolina.
Lisa A
LA
Wrage
Statistics and Epidemiology Unit, RTI International, Research Triangle Park, North Carolina.
Tracy L
TL
Nolen
Pharmacology and Toxicology Division, RTI International, Research Triangle Park, North Carolina.
Timothy R
TR
Fennell
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.
Richard A
RA
Ehrenkranz
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
Brenda B
BB
Poindexter
Department of Pediatrics, Duke University, Durham, North Carolina.
C
C
Michael Cotten
1] Department of Pediatrics, University of Oulu, Oulu, Finland [2] Oulu University Hospital, Oulu, Finland.
Mikko K
MK
Hallman
Division of Newborn Medicine, Department of Pediatrics, Floating Hospital for Children, Tufts Medical Center, Boston, Massachusetts.
Ivan D
ID
Frantz
Department of Pediatrics, Division of Neonatology, School of Medicine, University of Utah, Salt Lake City, Utah.
Roger G
RG
Faix
Statistics and Epidemiology Unit, RTI International, Research Triangle Park, North Carolina.
Kristin M
KM
Zaterka-Baxter
Statistics and Epidemiology Unit, RTI International, Rockville, Maryland.
Abhik
A
Das
Division of Neonatal and Developmental Medicine, Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University School of Medicine, Palo Alto, California.
M
M
Bethany Ball
Wake Forest University School of Medicine, Winston-Salem, North Carolina.
T
T
Michael O'Shea
University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
Conra
C
Backstrom Lacy
Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio.
Michele C
MC
Walsh
Department of Pediatrics, Wayne State University, Detroit, Michigan.
Seetha
S
Shankaran
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
Pablo J
PJ
Sánchez
Department of Pediatrics, University of Iowa, Iowa City, Iowa.
Edward F
EF
Bell
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
Rosemary D
RD
Higgins
D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007262:Infusions, Intravenous; D007294:Inositol / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D010919:Placebos; D012127:Respiratory Distress Syndrome, Newborn / Q000188:drug therapy*
D010919:Placebos; D007294:Inositol