Pharmacokinetics, pharmacodynamics and metabolism of caffeine in newborns

The plasma elimination half-life of caffeine in the newborn is approximately 100 h. Caffeine is rapidly absorbed with complete bioavailability following oral dosing. Switching between parenteral and oral administration requires no dose adjustments. Caffeine has wide interindividual pharmacodynamic variability and a wide therapeutic index in preterm newborns. Thresholds of measurable efficacy on respiratory drive have been documented at plasma levels around 2 mg/L. At these low levels, caffeine competitively inhibits adenosine receptors (A1 and A2A). The toxicity threshold is ill-defined and possibly as high as 60 mg/L which can be lethal in adults. High doses of caffeine may produce better control of apnea. However, at high systemic drug concentrations, the pharmacodynamic actions of caffeine become more complex and worrisome. They include inhibition of GABA receptors and cholinergic receptors in addition to adenosine receptor inhibition, intracellular calcium mobilization and actions on adrenergic, dopaminergic and phosphodiesterase systems. The role of pharmacogenomic factors as determinants of neonatal pharmacologic response and clinical effects remains to be explored.