Browsing by Author "Williams, Rick L."

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    Pharmacokinetics and safety of a single intravenous dose of myo-inositol in preterm infants of 23-29 wk
    (Springer Nature, 2013) 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.; Cotten, C. Michael; Hallman, Mikko K.; Frantz, Ivan D., III; Faix, Roger G.; Zaterka-Baxter, Kristin M.; Das, Abhik; Ball, M. Bethany; O'Shea, T. Michael; Backstrom Lacy, Conra; Walsh, Michele C.; Shankaran, Seetha; Sánchez, Pablo J.; Bell, Edward F.; Higgins, Rosemary D.; Pediatrics, School of Medicine
    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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    Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants
    (SpringerNature, 2016-08) 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 III, 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.; Department of Pediatrics, IU School of Medicine
    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.