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

Abstract

BACKGROUND Preterm infants with RDS given inositol had reduced BPD, death and severe ROP. We assessed the safety and pharmacokinetics(PK) 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 ≤29wks GA (n=122, 14 centers) were randomized and treated with placebo or inositol at 10, 40 or 80mg/kg/day. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 weeks, 34weeks PMA or discharge. Serum collection employed a sparse sampling population PK design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored. RESULTS At 80mg/kg/day mean serum levels reached 140mg/L, similar to Hallman’s findings. Levels declined after 2 weeks, converging in all groups by 6 wks. Analyses showed a mean volume of distribution 0.657 L/kg, clearance 0.058 L/kg/hr, and half-life 7.90 hr. Adverse events and co-morbidities were fewer in the inositol groups, but not significantly so. CONCLUSIONS Multiple dose inositol at 80mg/kg/day was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a Phase 3 trial.

Inositol and antioxidant supplementation: Safety and efficacy in pregnancy

“…Myo has been used in preterm infants (<29 weeks of gestational age) with respiratory distress syndrome in order to assess safety and pharmacokinetics of different daily inositol doses (10, 40, or 80 mg/kg/d). In this setting, treatment with Myo 80 mg/Kg/die for more than 10 weeks did not result in increased incidence of any adverse event as compared with control babies …”

Effects ofMyo-inositol on Type 1 Retinopathy of Prematurity Among Preterm Infants &lt;28 Weeks’ Gestational Age

“…The dose of myo-inositol to produce serum concentrations was similar to those in the previous studies. 5,6,15 However, the combination of longer treatment and the inclusion of infants with younger gestational ages may have resulted in the unexpected increase in mortality through as yet unknown mechanisms. In vitro data have shown that infection of macrophages by some intracellular bacteria is enhanced by their ability to use myo-inositol as an energy source.…”

“…After conducting pharmacokinetic and safety studies of myo-inositol in extremely preterm infants, a dose of 40 mg/kg every 12 hours was selected to achieve serum concentrations similar to those previously reported. 14,15 A therapeutic duration of up to 10 weeks was chosen to sustain serum myo-inositol levels similar to those found in utero throughout the period of normal retinal vascular development and because of the reported benefits in the treatment of ROP and survival. 12 The placebo was a solution of 5% glucose for intravenous infusion from pharmacy stock.…”

Unanticipated Deaths in Randomized Controlled Trials of Very Premature Infants

“…After contemporary evaluations of the pharmacokinetics of inositol in preterm infants, a recent RCT was suspended at 36% enrollment because of a manufacturing problem with the drug. 21,22 Of note, inositol is a nutritional supplement that can be used without oversight by the US Food and Drug Administration, although a parenteral form of the sugar is not available. On review by the DSMC, death was increased from 11% with the placebo to 18% with inositol supplementation (P = .007), severe retinopathy was qualitatively but not statistically increased, and there was no effect on BPD.…”