Single-Dose Intravenous Inositol Pharmacokinetics in Preterm Infants

Retinopathy of prematurity (ROP) is an abnormal growth of the blood vessels in the eye that
occurs primarily in very premature infants. Eye development occurs normally in the womb; in
infants born prematurely, however, the blood vessels must finish developing outside the
protective environment of the uterus. Retinopathy of prematurity (also known as retrolental
fibroplasia) is a leading cause of blindness and other vision impairments (myopia,
strabismus, and amblyopia) in children, both in developed and developing countries.

Inositol is a naturally-occurring sugar alcohol produced by the placenta and is present in
high levels in fetal blood throughout pregnancy in humans and other animals. Serum levels
fall rapidly after birth, although this fall is moderated in infants who receive breast
milk. Two randomized trials have shown that intravenous inositol supplementation in the
first week significantly reduced death, bronchopulmonary dysplasia (BPD), and retinopathy.
One study of oral supplements was less convincing, but also supported reduction of
retinopathy.

This pilot study evaluated the half-life pharmacokinetics of a single-dose of myo-inositol
(provided by Ross Products Division, Abbott Laboratories) in very low birth weight infants,
looking at changes in blood and urine inositol levels. The premise is that maintaining
inositol concentrations similar to those occurring naturally in utero will reduce the rates
of retinopathy and bronchopulmonary dysplasia in premature infants. Results from this study
will be used to select the doses for a subsequent multi-dose pilot study, and for the
planned large multi-center trials.

In this study, nine NICHD Neonatal Research Network sites enrolled 74 infants of less than
30 weeks gestation and randomly assigned them to receive either 60mg/kg of 5% inositol, 120
mg/kg of 5% inositol, 60 mg/kg of 5% glucose (the placebo), or 120 mg/kg of 5% glucose.
Concentrations of inositol were measured in both blood and urine to determine population
pharmacokinetic parameters for these infants.

Stratification: Enrolled infants were stratified by age with 37 infants of 23 0/7 to 26 6/7
weeks in one group and 37 infants of 27 0/7 to 29 6/7 weeks in a second group.

Inclusion Criteria:

- 23 0/7 to 26 6/7 weeks gestational age (36 infants) or

- 27 0/7 to 29 6/7 weeks gestational age (36 infants)

- 600-1500 grams birth weight

- No enteral feedings since birth at enrollment

- 3-6 days (25-132 hours) postnatal age

Note: Because of the high mortality expected in this population (15-20%), the study design
(originally for 72 infants) required recruitment of a replacement subject if any infant
failed to complete the four blood samples during the first week of the study.

Exclusion Criteria:

- Major congenital anomalies

- Moribund or not to be provided continued support

- Renal failure suspected (creatinine >2.5 with oliguria)

- Exchange transfusion received or expected to receive