Age-related amrinone pharmacokinetics in a pediatric population.
OBJECTIVE
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.


METHODS
Prospective study.


METHODS
A pediatric intensive care unit in a tertiary care teaching hospital.


METHODS
Thirty-one patients aged 4 days to 15 yrs who required a constant infusion of amrinone.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Allen-Webb
E M
EM
Department of Pediatrics, University of Utah, Salt Lake City.
Ross
M P
MP
Pappas
J B
JB
McGough
E C
EC
Banner
W
W
D000293:Adolescent; D000375:Aging / Q000378:metabolism*; D000676:Amrinone / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D006207:Half-Life; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D007668:Kidney / Q000378:metabolism; D016014:Linear Models; D008099:Liver / Q000378:metabolism; D008657:Metabolic Clearance Rate
D000676:Amrinone