Physiologically Based Pharmacokinetic (PBPK) Modeling of Caffeine and Theophylline in Neonates and Adults: Implications for Assessing Children's Risks from Environmental Agents

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Abstract
Children's risks can differ from those in adults for numerous reasons, one being differences in the pharmacokinetic handling of chemicals. Immature metabolism and a variety of other factors in neonates can affect chemical disposition and clearance. These factors can be incorporated into physiologically based pharmacokinetic (PBPK) models that simulate the fate of environmental toxicants in both children and adults. PBPK models are most informative when supported by empirical data, but typically pediatric pharmacokinetic data for toxicants are not available. In contrast, pharmacokinetic data in children are readily available for therapeutic drugs. The current analysis utilizes data for caffeine and theophylline, closely related xanthines that are both cytochrome P-450 (CYP) 1A2 substrates, in developing PBPK models for neonates and adults. Model development involved scale-up of in vitro metabolic parameters to whole liver and adjusting metabolic function for the ontological pattern of CYP1A2 and other CYPs. Model runs were able to simulate the large differences in half-life and clearance between neonates and adults. Further, the models were able to reproduce the faster metabolic clearance of theophylline relative to caffeine in neonates. This differential between xanthines was found to be due primarily to an extra metabolic pathway available to theophylline, back-methylation to caffeine, that is not available to caffeine itself. This pathway is not observed in adults exemplifying the importance of secondary or novel routes of metabolism in the immature liver. Greater CYP2E1 metabolism of theophylline relative to caffeine in neonates also occurs. Neonatal PBPK models developed for these drugs may be adapted to other CYP1A2 substrates (e.g., arylamine toxicants). A stepwise approach for modeling environmental toxicants in children is proposed.