Pharmacokinetics and safety of a single intravenous dose of myo-inositol in preterm infants of 23-29 wk

Abstract

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).

Conclusion: A single-compartment model accounting for endogenous production satisfactorily described the PK of i.v. inositol.

Figure 1. Consort Diagram: Flow of enrolled, randomized and analyzed subjects

^a Two infants started feeding prior to randomization; 1 infant’s condition worsened prior to randomization resulting in loss of vascular access required for drug administration. ^b Two infants identified as ineligible post-randomization (1 had < 600 grams birth weight, 1 developed severe IVH post-consent) ^c One infant received placebo in error, samples included as placebo in the pharmacokinetic (PK) analyses, however clinical outcomes included as intention to treat.

Figure 2. Serum Inositol Levels by Dose Group

Samples were collected within scheduled windows, plus additional scavenged samples as available. For this graph, collection times were clustered as follows to obtain mean values: 0 h (baseline) = obtained prior to infusion; 0.3 h (end of infusion) = 0–2 h post-infusion; 4 h = 2–6 h post-infusion; 8 h = 6–10 h post-infusion; 12 h = 10–14 h post-infusion; 24 h= 14–30 h post-infusion; 36 h = 30–42 h post-infusion; 48 h = 43–60 h post-infusion; 72 h = 60–82 h post-infusion; 96 h = >82 h post-infusion. Square = placebo, circle = 60mg/kg, triangle= 120mg/kg, vertical bar = ± 1 SD.

Figure 3. Observed vs. Individual Predicted Inositol Concentrations from the Pop-PK Analysis

Predicted values were calculated for each observed data point using the individual characteristics in the model described in the PK section of the text.

Figure 4. Predicted Serum Inositol Model

The model described in the PK section (before covariates) was used to predict the pattern of serum levels for a typical infant given repeated doses of 80 mg/kg/day divided into 40 mg/kg every 12 h for 36 h.