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Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants
Dale L Phelps1, Robert M Ward2, Rick L Williams3
1Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York.
Insights
Daily inositol supplementation at 80 mg/kg/d in preterm infants is safe and achieves beneficial serum levels. This dose is suitable for further investigation in Phase III trials for respiratory distress syndrome.
Area of Science:
- Neonatal Medicine
- Pharmacology
- Biochemistry
Background:
- Preterm infants with respiratory distress syndrome (RDS) may benefit from inositol.
- Previous studies suggest inositol reduces bronchopulmonary dysplasia (BPD), death, and severe retinopathy of prematurity (ROP).
- This study aimed to assess inositol safety and pharmacokinetics in preterm infants.
Purpose of the Study:
- To determine the optimal daily dose of inositol for preterm infants.
- To achieve serum inositol levels previously associated with therapeutic benefits.
- To evaluate inositol accumulation during the period of retinal vascularization.
Main Methods:
- A randomized trial involving 122 infants (≤ 29 weeks gestational age) across 14 centers.
- Infants received placebo or inositol (10, 40, or 80 mg/kg/d) intravenously, transitioning to enteral administration.
- Pharmacokinetic analysis used sparse sampling; safety and urine losses were monitored.
Main Results:
- The 80 mg/kg/d dose achieved mean serum levels of 140 mg/l, consistent with prior findings.
- Serum levels decreased after 2 weeks and converged by 6 weeks, indicating no significant accumulation.
- Adverse events and comorbidities were numerically lower in inositol groups, though not statistically significant.
Conclusions:
- Multiple-dose inositol at 80 mg/kg/d is safe for preterm infants.
- This dosage achieves effective serum concentrations without significant accumulation.
- The findings support further investigation of this inositol regimen in Phase III trials.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
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