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Masoud JameiMasoud Jamei is a senior scientific advisor and the head of Modelling and Simulation at Simcyp, a Certara company, and a visiting senior lecturer at the University of Manchester. His current research is concerned with development of physiologically based pharmacokinetic (PBPK) models. Bridging bottom-up and top-down paradigms and their applications in PBPK models is another facet of his research activities.

Drug companies often develop and test drugs for and in adults, but because of ethical issues drugs often undergo limited or no testing in children. Despite this, prescribing adult drugs for children is common, but selecting the right dose to give to an individual child can be difficult. Generally, patient body weight is used as an indicator of the body’s ability to eliminate drugs, and dose adjustments are made using the body weight of the child. As an alternative, and in particular in certain therapeutic areas such as cancer, drugs are dosed to children based on their body surface area. Nonetheless, no single method is suitable across the entire pediatric age range, and the current paradigm for selecting drug dose in children does not guarantee safe and effective treatment.

Apart from body size, many biological and physiological processes that affect the fate of drugs in the body (e.g., plasma protein concentration, levels of active drug metabolizing enzymes, changes in organ blood flow, etc.) evolve as children mature. Therefore, these processes should be taken into account when selecting the correct drug dose in children. Physiologically based pharmacokinetic (PBPK) models are a useful tool for integrating available prior knowledge of changes in the biology and physiology of children as they grow and have been applied to better design pediatric trials and better determine drug dose in children. There are reports of successful application of PBPK methods to predict drug clearance in children, and the Food and Drug Administration (FDA) has also reported receiving regulatory submissions using pediatric PBPK models. Despite the successful application of PBPK models to predict drug disposition in children, more research in this area is needed, and to date the applications of pediatric PBPK models have been limited to small molecules.

Biologic drugs are suitable for children because they offer more convenient (less frequent) dosing regimens in comparison with small molecules. Further, because their action is targeted, at least in theory, organ toxicity is less likely to happen. But there is still no widely accepted method for determining dosing of biologics in children.

In a similar scenario to that already applied for small molecules, PBPK models may also be suitable to guide dosing of biologics in children. Much of the data already collected for PBPK models of small molecules can be directly used for developing PBPK models of biologics. Specific factors that could lead to differences in pharmacokinetics of proteins and peptides in children include levels and rates of catabolic enzymes, changes in body composition, function of elimination organs, the concentration of FcRn, levels of pharmacological target, lymph flow, the size of pores in blood vessel endothelium, and rates of receptor mediated endocytosis. These changes can lead to changes in the volume of distribution, clearance, and absorption of biologics.

To identify the knowledge gaps in this area, the hot topic session Physiologically Based Modeling of Biologics in Pediatrics: Where Are the Holes? on May 19 at the AAPS National Biotechnology Conference will involve experts who will discuss the latest developments and future directions in this important area.