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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.

SUBMITTER: Phelps DL

PROVIDER: S-EPMC5198845 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants.

Phelps Dale L DL Ward Robert M RM Williams Rick L RL Nolen Tracy L TL Watterberg Kristi L KL Oh William W Goedecke Michael M Ehrenkranz Richard A RA Fennell Timothy T Poindexter Brenda B BB Cotten C Michael CM Hallman Mikko M Frantz Ivan D ID Faix Roger G RG Zaterka-Baxter Kristin M KM Das Abhik A Ball M Bethany MB Lacy Conra Backstrom CB Walsh Michele C MC Carlo Waldemar A WA Sánchez Pablo J PJ Bell Edward F EF Shankaran Seetha S Carlton David P DP Chess Patricia R PR Higgins Rosemary D RD

Pediatric research 20160413 2

<h4>Background</h4>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.<h4>Methods</h4>Infants ≤ 29 wk GA (n = 122, 14 centers) were ...[more]

PMID: 27074126

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Project description:Importance:Previous studies of myo-inositol in preterm infants with respiratory distress found reduced severity of retinopathy of prematurity (ROP) and less frequent ROP, death, and intraventricular hemorrhage. However, no large trials have tested its efficacy or safety. Objective:To test the adverse events and efficacy of myo-inositol to reduce type 1 ROP among infants younger than 28 weeks' gestational age. Design, Setting, and Participants:Randomized clinical trial included 638 infants younger than 28 weeks' gestational age enrolled from 18 neonatal intensive care centers throughout the United States from April 17, 2014, to September 4, 2015; final date of follow-up was February 12, 2016. The planned enrollment of 1760 participants would permit detection of an absolute reduction in death or type 1 ROP of 7% with 90% power. The trial was terminated early due to a statistically significantly higher mortality rate in the myo-inositol group. Interventions:A 40-mg/kg dose of myo-inositol was given every 12 hours (initially intravenously, then enterally when feeding; n = 317) or placebo (n = 321) for up to 10 weeks. Main Outcomes and Measures:Type 1 ROP or death before determination of ROP outcome was designated as unfavorable. The designated favorable outcome was survival without type 1 ROP. Results:Among 638 infants (mean, 26 weeks' gestational age; 50% male), 632 (99%) received the trial drug or placebo and 589 (92%) had a study outcome. Death or type 1 ROP occurred more often in the myo-inositol group vs the placebo group (29% vs 21%, respectively; adjusted risk difference, 7% [95% CI, 0%-13%]; adjusted relative risk, 1.41 [95% CI, 1.08-1.83], P = .01). All-cause death before 55 weeks' postmenstrual age occurred in 18% of the myo-inositol group and in 11% of the placebo group (adjusted risk difference, 6% [95% CI, 0%-11%]; adjusted relative risk, 1.66 [95% CI, 1.14-2.43], P = .007). The most common serious adverse events up to 7 days of receiving the ending dose were necrotizing enterocolitis (6% for myo-inositol vs 4% for placebo), poor perfusion or hypotension (7% vs 4%, respectively), intraventricular hemorrhage (10% vs 9%), systemic infection (16% vs 11%), and respiratory distress (15% vs 13%). Conclusions and Relevance:Among premature infants younger than 28 weeks' gestational age, treatment with myo-inositol for up to 10 weeks did not reduce the risk of type 1 ROP or death vs placebo. These findings do not support the use of myo-inositol among premature infants; however, the early termination of the trial limits definitive conclusions.

Dataset Information

Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants.

Publications

Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants.

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