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 (BPD) and reduced severe retinopathy of prematurity (ROP) in 2 randomized trials. Pharmacokinetic (PK) studies in extremely preterm infants are needed prior to efficacy trials. Methods Infants of 23–29 weeks gestation were randomized to a single intravenous (IV) 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 1-compartment model that included factors for endogenous inositol production, allometric size based on weight, gestational age (GA) strata and creatinine clearance fit the data best. The central volume of distribution was 0.5115 l/kg, the clearance 0.0679 l/kg/h, endogenous production 2.67 mg/kg/h and the half life 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 after 48 h. There was no diuretic side-effect. No significant differences in adverse events occurred between the 3 groups (p > 0.05). Conclusions A single compartment model accounting for endogenous production satisfactorily described the PK of IV inositol.

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

“…The data thus correspond to observations related to the multiple IV administrations and are referred to as the multiple-administration dataset. The single-dose data previously analyzed were included in parts of the analysis and will be referred to as the single-administration dataset(5). Both studies were conducted by the same investigators in the same research network using protocols consistent across both studies except for the repeated dosing.…”

“…Howlett concluded in a Cochrane meta-analysis of inositol in preterm infants, “that a multi-center, randomized controlled trial of appropriate size is warranted to confirm these findings”(4). We reported the PK of a single dose of IV inositol in preterm infants at doses of 60mg/kg or 120mg/kg, and found the half-life was 5.22hr, with large urine losses, particularly in the first 12hr after dosing(5). Our 3 goals were to identify a daily dose to achieve serum levels similar to those reported by Hallman, [170mg/L (994μmole/L) at 8–9 days for infants given 160mg/kg/day, and an approximate mean value over the first week of life of 135mg/L (750μmole/L) when receiving 80mg/kg/day(2,6)]; to learn if divided doses would reduce urine losses; and to assure safety with up to 10 weeks of treatment.…”

A systematic review of randomized controlled trials for the prevention of bronchopulmonary dysplasia in infants

“…A recently published study also adds information regarding the pharmacokinetics of inositol in preterm infants. 36 A single trial of clarithromycin in 68 infants evaluated a primary outcome of eradication of Ureaplasma urealyticum and the secondary outcome of incidence of BPD, defined as oxygen requirement at 36 weeks PMA (2.9% incidence in those treated with clarithromycin vs. 36.4% in those not treated; p<0.001). 37 While clarithromycin does have FDA-labeled indications for a variety of infectious diseases, it is not approved for use in infants <6 months of age.…”

Methodological issues in the design and analyses of neonatal research studies: Experience of the NICHD Neonatal Research Network

“…In addition, our model efficiently combined the sparse repeated measures data from each infant using population-PK methods based on nonlinear mixed effects models. 80 …”