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

Dale L. Phelps, Robert M. Ward, Rick L. Williams, Tracy L. Nolen, Kristi L. Watterberg, William Oh, Michael Goedecke, Richard A. Ehrenkranz, Timothy Fennell, Brenda B. Poindexter, C. Michael Cotten, Mikko Hallman, Ivan D. Frantz, Roger G. Faix, Kristin M. Zaterka-Baxter, Abhik Das, M. Bethany Ball, Conra Backstrom Lacy, Michele C. Walsh, Waldemar A. Carlo & 6 others Pablo J. Sánchez, Edward F. Bell, Seetha Shankaran, David P. Carlton, Patricia R. Chess, Rosemary D. Higgins

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)209-217
Number of pages9
JournalPediatric Research
Volume80
Issue number2
DOIs
StatePublished - Aug 1 2016

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Inositol
Premature Infants
Pharmacokinetics
Safety
Serum
Newborn Respiratory Distress Syndrome
Bronchopulmonary Dysplasia
Retinopathy of Prematurity
Enteral Nutrition
Intravenous Administration
Half-Life
Comorbidity
Placebos
Urine
Population

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Phelps, D. L., Ward, R. M., Williams, R. L., Nolen, T. L., Watterberg, K. L., Oh, W., ... Higgins, R. D. (2016). Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants. Pediatric Research, 80(2), 209-217. https://doi.org/10.1038/pr.2016.97

Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants. / Phelps, Dale L.; Ward, Robert M.; Williams, Rick L.; Nolen, Tracy L.; Watterberg, Kristi L.; Oh, William; Goedecke, Michael; Ehrenkranz, Richard A.; Fennell, Timothy; Poindexter, Brenda B.; Cotten, C. Michael; Hallman, Mikko; Frantz, Ivan D.; Faix, Roger G.; Zaterka-Baxter, Kristin M.; Das, Abhik; Ball, M. Bethany; Lacy, Conra Backstrom; Walsh, Michele C.; Carlo, Waldemar A.; Sánchez, Pablo J.; Bell, Edward F.; Shankaran, Seetha; Carlton, David P.; Chess, Patricia R.; Higgins, Rosemary D.

In: Pediatric Research, Vol. 80, No. 2, 01.08.2016, p. 209-217.

Research output: Contribution to journalArticle

Phelps, DL, Ward, RM, Williams, RL, Nolen, TL, Watterberg, KL, Oh, W, Goedecke, M, Ehrenkranz, RA, Fennell, T, Poindexter, BB, Cotten, CM, Hallman, M, Frantz, ID, Faix, RG, Zaterka-Baxter, KM, Das, A, Ball, MB, Lacy, CB, Walsh, MC, Carlo, WA, Sánchez, PJ, Bell, EF, Shankaran, S, Carlton, DP, Chess, PR & Higgins, RD 2016, 'Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants', Pediatric Research, vol. 80, no. 2, pp. 209-217. https://doi.org/10.1038/pr.2016.97
Phelps DL, Ward RM, Williams RL, Nolen TL, Watterberg KL, Oh W et al. Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants. Pediatric Research. 2016 Aug 1;80(2):209-217. https://doi.org/10.1038/pr.2016.97
Phelps, Dale L. ; Ward, Robert M. ; Williams, Rick L. ; Nolen, Tracy L. ; Watterberg, Kristi L. ; Oh, William ; Goedecke, Michael ; Ehrenkranz, Richard A. ; Fennell, Timothy ; Poindexter, Brenda B. ; Cotten, C. Michael ; Hallman, Mikko ; Frantz, Ivan D. ; Faix, Roger G. ; Zaterka-Baxter, Kristin M. ; Das, Abhik ; Ball, M. Bethany ; Lacy, Conra Backstrom ; Walsh, Michele C. ; Carlo, Waldemar A. ; Sánchez, Pablo J. ; Bell, Edward F. ; Shankaran, Seetha ; Carlton, David P. ; Chess, Patricia R. ; Higgins, Rosemary D. / Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants. In: Pediatric Research. 2016 ; Vol. 80, No. 2. pp. 209-217.
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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.",
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T1 - Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants

AU - Phelps, Dale L.

AU - Ward, Robert M.

AU - Williams, Rick L.

AU - Nolen, Tracy L.

AU - Watterberg, Kristi L.

AU - Oh, William

AU - Goedecke, Michael

AU - Ehrenkranz, Richard A.

AU - Fennell, Timothy

AU - Poindexter, Brenda B.

AU - Cotten, C. Michael

AU - Hallman, Mikko

AU - Frantz, Ivan D.

AU - Faix, Roger G.

AU - Zaterka-Baxter, Kristin M.

AU - Das, Abhik

AU - Ball, M. Bethany

AU - Lacy, Conra Backstrom

AU - Walsh, Michele C.

AU - Carlo, Waldemar A.

AU - Sánchez, Pablo J.

AU - Bell, Edward F.

AU - Shankaran, Seetha

AU - Carlton, David P.

AU - Chess, Patricia R.

AU - Higgins, Rosemary D.

PY - 2016/8/1

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N2 - 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.

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