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

Dale L. Phelps, Robert M. Ward, Rick L. Williams, Kristi L. Watterberg, Abbot R. Laptook, Lisa A. Wrage, Tracy L. Nolen, Timothy R. Fennell, Richard A. Ehrenkranz, Brenda B. Poindexter, C. Michael Cotten, Mikko K. Hallman, Ivan D. Frantz, Roger G. Faix, Kristin M. Zaterka-Baxter, Abhik Das, M. Bethany Ball, T. Michael O'Shea, Conra Backstrom Lacy, Michele C. Walsh & 4 others Seetha Shankaran, Pablo J. Sánchez, Edward F. Bell, Rosemary D. Higgins

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)721-729
Number of pages9
JournalPediatric Research
Volume74
Issue number6
DOIs
StatePublished - Dec 2013

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Inositol
Premature Infants
Pharmacokinetics
Safety
Extremely Premature Infants
Bronchopulmonary Dysplasia
Retinopathy of Prematurity
Diuretics
Population
Gestational Age
Half-Life
Creatinine
Placebos
Urine
Weights and Measures
Pregnancy
Serum

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Phelps, D. L., Ward, R. M., Williams, R. L., Watterberg, K. L., Laptook, A. R., Wrage, L. A., ... Higgins, R. D. (2013). Pharmacokinetics and safety of a single intravenous dose of myo-inositol in preterm infants of 23-29 wk. Pediatric Research, 74(6), 721-729. https://doi.org/10.1038/pr.2013.162

Pharmacokinetics and safety of a single intravenous dose of myo-inositol in preterm infants of 23-29 wk. / Phelps, Dale L.; Ward, Robert M.; Williams, Rick L.; Watterberg, Kristi L.; Laptook, Abbot R.; Wrage, Lisa A.; Nolen, Tracy L.; Fennell, Timothy R.; Ehrenkranz, Richard A.; Poindexter, Brenda B.; Michael Cotten, C.; Hallman, Mikko K.; Frantz, Ivan D.; Faix, Roger G.; Zaterka-Baxter, Kristin M.; Das, Abhik; Bethany Ball, M.; Michael O'Shea, T.; Lacy, Conra Backstrom; Walsh, Michele C.; Shankaran, Seetha; Sánchez, Pablo J.; Bell, Edward F.; Higgins, Rosemary D.

In: Pediatric Research, Vol. 74, No. 6, 12.2013, p. 721-729.

Research output: Contribution to journalArticle

Phelps, DL, Ward, RM, Williams, RL, Watterberg, KL, Laptook, AR, Wrage, LA, Nolen, TL, Fennell, TR, Ehrenkranz, RA, Poindexter, BB, Michael Cotten, C, Hallman, MK, Frantz, ID, Faix, RG, Zaterka-Baxter, KM, Das, A, Bethany Ball, M, Michael O'Shea, T, Lacy, CB, Walsh, MC, Shankaran, S, Sánchez, PJ, Bell, EF & Higgins, RD 2013, 'Pharmacokinetics and safety of a single intravenous dose of myo-inositol in preterm infants of 23-29 wk', Pediatric Research, vol. 74, no. 6, pp. 721-729. https://doi.org/10.1038/pr.2013.162
Phelps DL, Ward RM, Williams RL, Watterberg KL, Laptook AR, Wrage LA et al. Pharmacokinetics and safety of a single intravenous dose of myo-inositol in preterm infants of 23-29 wk. Pediatric Research. 2013 Dec;74(6):721-729. https://doi.org/10.1038/pr.2013.162
Phelps, Dale L. ; Ward, Robert M. ; Williams, Rick L. ; Watterberg, Kristi L. ; Laptook, Abbot R. ; Wrage, Lisa A. ; Nolen, Tracy L. ; Fennell, Timothy R. ; Ehrenkranz, Richard A. ; Poindexter, Brenda B. ; Michael Cotten, C. ; Hallman, Mikko K. ; Frantz, Ivan D. ; Faix, Roger G. ; Zaterka-Baxter, Kristin M. ; Das, Abhik ; Bethany Ball, M. ; Michael O'Shea, T. ; Lacy, Conra Backstrom ; Walsh, Michele C. ; Shankaran, Seetha ; Sánchez, Pablo J. ; Bell, Edward F. ; Higgins, Rosemary D. / Pharmacokinetics and safety of a single intravenous dose of myo-inositol in preterm infants of 23-29 wk. In: Pediatric Research. 2013 ; Vol. 74, No. 6. pp. 721-729.
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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.",
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T1 - Pharmacokinetics and safety of a single intravenous dose of myo-inositol in preterm infants of 23-29 wk

AU - Phelps, Dale L.

AU - Ward, Robert M.

AU - Williams, Rick L.

AU - Watterberg, Kristi L.

AU - Laptook, Abbot R.

AU - Wrage, Lisa A.

AU - Nolen, Tracy L.

AU - Fennell, Timothy R.

AU - Ehrenkranz, Richard A.

AU - Poindexter, Brenda B.

AU - Michael Cotten, C.

AU - Hallman, Mikko K.

AU - Frantz, Ivan D.

AU - Faix, Roger G.

AU - Zaterka-Baxter, Kristin M.

AU - Das, Abhik

AU - Bethany Ball, M.

AU - Michael O'Shea, T.

AU - Lacy, Conra Backstrom

AU - Walsh, Michele C.

AU - Shankaran, Seetha

AU - Sánchez, Pablo J.

AU - Bell, Edward F.

AU - Higgins, Rosemary D.

PY - 2013/12

Y1 - 2013/12

N2 - 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.

AB - 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.

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