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

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.

Physiologically Based Pharmacokinetics of Matrine in the Rat after Oral Administration of Pure Chemical and ACAPHA

“…Even fewer PBPK models are developed for the botanical drug. As far as we know, only the following botanical drug PBPK models have been reported to date: soy isoflavones (Schlosser et al, 2006;Law, 2007a), tea catechins (Law, 2006(Law, , 2007b, caffeine (Ginsberg et al, 2004), sophoridine (Hu and Huang, 1995), and glycyrrhizic acid (Ploeger et al, 2000). PBPK models had been used to extrapolate dose-response relationships among species, routes of administration, and dosage regimens (Nestorov, 2003).…”

Expressing urine from a gel disposable diaper for biomonitoring using phthalates as an example

“…For example, the gastric emptying time increases and the intestinal motility decreases during pregnancy, which may result in longer retention of ingested xenobiotics in the upper intestinal tract, leading to the possibility for increased absorption of xenobiotics and increased exposure of the fetus (Klaassen, 1996). Cardiac output and peripheral blood flow al., de Zwart et al, 2004;Ginsberg et al, 2004c). Table 2 increase by approximately 30% during the first trimester of gestation.…”

“…In such cases, physiological modelling approaches that take into account the quantitative changes in physiological and biochemical determinants may be used to evaluate the agedependent change in target tissue dose of chemicals (Nong et al, 2006). The adult-child difference in susceptibility may be not only related to differences in target tissue dose but also due to toxicodynamics or the interaction between the toxic moiety and biological macromolecules in target tissues, resulting in the onset and progression of injury (Ginsberg et al, 2004c). The following section provides an overview of the functional and structural development of various organ systems as well as the molecular determinants associated with these processes.…”

“…Probabilistic assessments account for the range of interindividual variability and can be used to estimate the central tendency and upper bound of internal dose. Toxicokinetic assessments can also provide an understanding of the mechanism of toxicity by providing various estimates of internal dose that can be correlated with health effects (Ginsberg et al, 2004c).…”

Examining Small Intestinal Transit Time as a Function of Age: Is There Evidence to Support Age-Dependent Differences among Children?

“…Correspondingly, simulations used an intestinal permeability of 4.4 Â 10 24 cm/s, a value that is qualitatively associated with high-permeability compounds (Lennernäs, 2014). In adults, theophylline clearance is a combination of hepatic metabolism (CYP1A2 and CYP2E1) and glomerular filtration (Ginsberg et al, 2004;Edginton et al, 2006). Utilizing the PBPK model framework, literature-based PK studies depicting concentration-time profiles following administration of theophylline either intravenously (Aslaksen et al, 1981;Horai et al, 1983) or orally (Rovei et al, 1982) as an immediate release formulation (assuming fraction absorbed = 1) were used to obtain specific estimates of hepatic and renal clearance in healthy adults.…”