By Rakesh Gollen and Varsha Bhatt-Mehta
Children are not small adults! This phrase has been used by many when referring to use of medications in pediatric patients. It is well recognized that pediatric patients handle medications very differently compared with adults. According to a survey supported by the National Institutes of Health (NIH), there are millions of children who are prescribed medications that don’t have any data on pediatric efficacy or safety.
Drugs are administered in a variety of therapeutic areas using extrapolated dosing data from adult dosing in studies. Recent AAPS Blog posts on pediatric population by Andrew Porterfield, Varsha Bhatt-Mehta, and Prathap Shastri and Jaydeep Yadav emphasize this fact. In the past three decades, much attention has been focused across the globe on the need for expanding pediatric pharmaceutical research. Here we highlight some of the key issues related to development of drug dosing in pediatric patients, including physiologic changes and how they affect the absorption, distribution, metabolism, and excretion (ADME) of drugs. ADME parameters, which are determinants of pharmacokinetics, pharmacodynamics, safety, and efficacy of a drug, are often reported in the literature without any consideration for the influence of simultaneous, ongoing physiologic changes due to growth in children.
Within the pediatric population, ADME varies by the age of the child. This necessitates studying appropriate dosage forms in various age groups, keeping in mind not only ADME but also the simultaneous physiologic changes that are ongoing, which may influence ADME at any given time. Population pharmacokinetic modeling and simulation provides information about ADME but lacks the inclusion of simultaneous physiologic changes that may be occurring and influencing ADME.
Absorption for orally administered medication is known to be affected by many age-related changes in gastric acid secretion, bile salt formation, gastric emptying time, intestinal motility, bowel length, and effective absorptive surface. Distribution of drugs also varies due to age-related changes in body composition (especially the extracellular and total body water spaces) as well as drug binding to proteins (primarily albumin, α 1 -acid glycoprotein, and lipoproteins), which also plays a key role in drug distribution. Metabolism of various drugs also varies with age as phase 1 activity is reduced in neonates, increases progressively during the first six months after birth, and reaches the adult values by teenage years. CYP450 activity can also be induced (reducing drug concentrations and effect, thus compromising efficacy) or inhibited (augmenting concentrations and effect, which may compromise safety). On the other hand, renal elimination of drugs primarily depends on plasma protein binding, renal blood flow, glomerular filtration rate, and tubular secretion, which changes significantly during the first two years after birth.
Thus, for pediatric patients, ranging in age from premature infants to adolescents, it is important to use models that include physiologic maturation as a function of time. In this respect, physiologically-based pharmacokinetic modeling (PBPK) is much more informative to predict the drug disposition among these specific populations. If you are using these approaches, please feel free to share your views. In our next blog we will discuss the comparison of PBPK and population PK/PD approach used in pediatric drug development.