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

• Authors: Dale L. Phelps, University of Rochester; Robert M. Ward, University of Utah; Rick L. Williams, RTI International; Tracy L. Nolen, RTI International; Kristi L. Watterberg, University of New Mexico; William Oh, Brown University; Michael Goedecke, RTI International; Richard A. Ehrenkranz, Yale University; Timothy Fennell, RTI International; Brenda B. Poindexter, Indiana Univ Sch Med; C. Michael Cotten, Duke University; Mikko Hallman, PEDEGO Res Ctr; Ivan D. Frantz, Floating Hosp Children; Roger G. Faix, University of Utah; Kristin M. Zaterka-Baxter, RTI International; Abhik Das, RTI International; M. Bethany Ball, Stanford University; Conra B. Lacy, University of New Mexico; Michele C. Walsh, Case Western Reserve University; Waldemar A. Carlo, University of Alabama Birmingham; Pablo J. Sanchez, Univ Texas Southwestern Med Ctr Dallas; Edward F. Bell, University of Iowa; Seetha Shankaran, Wayne State University; David Carlton, Emory University; Patricia R. Chess, University of Rochester; Rosemary D. Higgins, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum
• Journal Title: Pediatric Research
• Volume: Volume 80, Number 2
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option A | 2016-08-01, Pages 209-217
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/pr.2016.97
• Subjects: Health Sciences, General; Health Sciences, Pharmacology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Pediatrics; RESPIRATORY-DISTRESS-SYNDROME; INOSITOL SUPPLEMENTATION; PREMATURITY; RETINOPATHY

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.