By: Narasimha Midde, PhD
The majority of the marketed drugs are not adequately assessed to use in children because of ethical, practical, and scientific constraints. It is estimated that off-label or un-licensed use of drugs in pediatric population is up to 70% in children and 92% in neonates1, 2. It is an established fact that drug disposition and response to drug exposure differ not only between children and adults but also within children of different ages3, 4. These differences are not only due to developmental changes in body composition and size, but also due to changes in drug metabolizing enzymes and transporters expression and function. The primary goal of drug metabolizing enzymes is to make the drug more water soluble to facilitate its elimination from the body. This process is predominately accomplished in two phases, Phase I, structural changes to the drug molecule by cytochrome P450 (CYP) enzymes, and Phase II, conjugation with other more water-soluble molecules.
The relevant CYPs in Phase I metabolism are mainly CYP3A4, 3A5, 3A7, 2C9, 2C19, 2D6, 1A2, 2E1, and 2B6. The expression and function of these enzymes are not linear with age, especially in younger ages. Therefore, scaling dose from adults to young children (< 5 years) using weight-based models may potentially result in of a drug that is predominately metabolized by a particular CYP enzyme that had not attained adult-level in expression and function5, 6. For example, caffeine metabolism is low in neonates but increases in infants as CYP1A2 – the major enzyme responsible for caffeine metabolism – develops.
Similar to CYPs, enzymes that are involved in the Phase II reactions do not follow a linear pattern to develop with age. However, developmental data for these enzymes is limited. Several drugs that are commonly used in children are metabolized through uridine 5-diphosphoglucuronic acid glucuronyl transferases (UGTs). For instance, morphine is primarily metabolized by UGT2B7, which is low in neonates and increased by 2-6 months of age. In this case, the weight-based dose calculations will result in doses higher than required. In contrast, although acetaminophen transformation by UGT is lower in neonates, another Phase II enzyme sulfotransferase converts it into the sulfate conjugates, suggesting a compensatory mechanism to eliminate the drug from the body.
In conclusion, the complexity of maturation of drug metabolic pathways shows how weight-based extrapolation of dosing to children especially to infants and young children may lead to higher exposure and subsequent increased risk of drug toxicity. Therefore, it is not always advisable to dose children based on adult studies. Modeling and simulation methodologies like physiologically based pharmacokinetic (PBPK) and population pharmacokinetics with sparse sampling strategies will certainly help guiding dose selection in children and designing optimum pediatric studies that achieve maximum efficacy and safety.
- t Jong GW, et al. Unapproved and off-label use of drugs in a children’s hospital. N Engl J Med 343 1125. (2000)
- Roberts R, Rodriguez W, Murphy D, Crescenzi T. Pediatric drug labeling: improving the safety and efficacy of pediatric therapies. JAMA 290 905-911. (2003)
- Lu H, Rosenbaum S. Developmental pharmacokinetics in pediatric populations. J Pediatr Pharmacol Ther 19 262-276. (2014)
- Ku LC, Smith PB. Dosing in neonates: special considerations in physiology and trial design. Pediatr Res 77 2-9. (2015)
- FDA-Guidance. Guidance for Industry Nonclinical Safety Evaluation of Pediatric Drug Products
- Yaffe S. Rational Therapeutics for Infants and Children: Workshop Summary. In: Yaffe S (ed). Rational Therapeutics for Infants and Children: Workshop Summary: Washington (DC), 2000.
- Fernandez E, et al. Factors and Mechanisms for Pharmacokinetic Differences between Pediatric Population and Adults. Pharmaceutics 3 53-72. (2011)