Theophylline toxicokinetics in premature newborns

Background: While cytochrome P4501A2 is the primary pathway for theophylline (aminophylline ethylenediamine) metabolism in adults, it is developmentally immature in the newborn. Objective: To report the developmental differences in theophylline toxicokinetics of neonates. Design: Case series. Three premature neonates received inadvertent intravenous overdoses of theophylline for apnea of prematurity while in newborn intensive care. Maximum serum concentrations ranged from 55 to 123 mg/L. Theophylline-derived caffeine levels plateaued at 8.4 to 13 mg/L and did not decline during the sampling period. All newborns experienced sinus tachycardia and agitation. Sequential theophylline and caffeine serum levels were obtained periodically for 62 to 100 hours. In contrast to older children and adults, in whom theophylline disposition follows zero-order kinetics at high concentrations, a monoexponential function best described theophylline elimination 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 values are consistent with those previously reported in neonates. All patients were treated with supportive care without invasive procedures. No seizures or 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.