Theophylline toxicokinetics in premature newborns

Background: While cytochrome P4501A2 is the primary pathway for theophyllin e (aminophylline ethylenediamine) metabolism in adults, it is developmental ly immature in the newborn. Objective: To report the developmental differences in theophylline toxicoki netics of neonates. Design: Case series. Three premature neonates received inadvertent intraven ous overdoses of theophylline for apnea of prematurity while in newborn int ensive care. Maximum serum concentrations ranged from 55 to 123 mg/L. Theop hylline-derived caffeine levels plateaued at 8.4 to 13 mg/L and did not dec line during the sampling period. All newborns experienced sinus tachycardia and agitation. Sequential theophylline and caffeine serum levels were obta ined periodically for 62 to 100 hours. In contrast to older children and ad ults, in whom theophylline disposition follows zero-order kinetics at high concentrations, a monoexponential function best described theophylline elim ination in the premature newborn, with half-lives ranging from 24.7 to 36.5 hours and estimated clearance from 0.02 to 0.05 L/kg per hour. These value s are consistent with those previously reported in neonates. All patients w ere treated with supportive care without invasive procedures. No seizures o r apparent sequelae occurred. Conclusion: Developmental differences in the balance between nonrenal (ie, metabolic) and renal elimination pathways produce the unique toxicokinetics of theophylline in the neonate.