Age-related amrinone pharmacokinetics in a pediatric population

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Abstract
To measure the plasma concentrations of amrinone and N-acetyl-amrinone achieved using current pediatric dosing recommendations. To examine the pharmacokinetics of amrinone in an extended age range of pediatric patients. To examine any age-related differences in the relative contribution of hepatic metabolism vs. renal elimination of amrinone. Prospective study. A pediatric intensive care unit in a tertiary care teaching hospital. Thirty-one patients aged 4 days to 15 yrs who required a constant infusion of amrinone. Blood samples were obtained 15 mins after each 0.75 mg/kg loading dose, and every 6 hrs during a constant infusion of amrinone to measure plasma amrinone, N-acetyl-amrinone and N-glycolyl-amrinone concentrations by high-performance liquid chromatography. Blood samples to measure amrinone, N-acetyl-amrinone, and N-glycolyl-amrinone concentrations during elimination were also obtained at regular intervals after discontinuation of the infusion. Six-hour urine collections were obtained to measure amrinone renal clearance. Plasma amrinone concentrations > or = 2 micrograms/mL were obtained in 13 of 14 patients after a 3-mg/kg loading dose. There was a six-fold variability in steady-state plasma amrinone concentrations in patients receiving the same ordered infusion rate. There was a significant (p = .001) difference between the ordered and measured amrinone infusion rates. Six (19.4%) of 31 patients had steady-state plasma amrinone concentrations of < or = 2 micrograms/mL. There was a large variability in the volume of distribution, clearance, and elimination half-life which did not appear to be age-related. Renal clearance of amrinone ranged between 0.4 and 2.18 mL/kg/min, and did not increase with age. There was no increase in the proportion of children with a high plasma steady-state N-acetyl-amrinone/amrinone ratio over time from 1 to 24 months of life. Administering a 3-mg/kg amrinone loading dose in four divided doses over 1 hr resulted in relatively rapid therapeutic plasma concentrations without excessively high concentrations and good clinical tolerance. The wide interindividual variation in clearance and volume of distribution resulted in a variable dose-concentration relationship; children receiving lower amrinone infusion rates may-have subtherapeutic plasma steady-state concentrations. There did not appear to be any age-related change in renal clearance or hepatic metabolism of amrinone in children aged 1 to 24 months.

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