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

Abstract

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.

Figure 1. Consort Flow Sheet of Study Subjects

¹Reason unknown. ²One infant identified as ineligible post-randomization; two infants died. ³One placebo subject incorrectly received 10mg/kg/day of inositol for 7 days before it was discovered and stopped and is considered to be part of the 10m/kg/day group only for the PK analysis. However, other data from this subject are analyzed, as randomized, with the placebo infants.

Figure 2. Serum Inositol Levels

Mean±SD, by dose, clustered by days on study. Symbols: 80mg/kg/day = blue diamond, 40mg/kg/day = green triangle, 10mg/kg/day = orange circle, placebo = red square. Panel A includes all samples; panel B values only while subjects were receiving IV doses; panel C values obtained only when subjects were receiving enteral dosing. Timed samples were collected within scheduled windows (see Methods), plus additional scavenged laboratory residual samples as available and if exact timing after the previous dose was known for the sample. For presentation, collection days are clustered in mean values to simplify display: Study Day 0=baseline before 1^st infusion; Day 2= 1^st sample after 1^st infusion; day 3=3rd study day; day 4=4–5d; day 6=6–7d; day 8=8–9d; day 10=10–11d; day 12=12–13d; day 14=14–15d; day 16=16–18d; day 20=19–22d; day 24=23–26d; day 28=27–31d; day 35d=32–38d; day 42=39–48d; day 56=49–63d; day 70=64–77d. Plotting only peak values, or only trough levels did not assist in displaying the data.

Figure 3. Inositol Urine Losses

Inositol in the urine from each diaper (Concentration × Volume) was summed over 24hr to determine the urine losses, at weekly intervals. Data are mean±SD, and slightly offset for better visualization. Symbols: Square=placebo, circle=10mg/kg/day, triangle=40mg/kg/day and diamond=80mg/kg/day.