Leveraging PBPK Modeling and Simulation for Neonatal and Infant Drug Development

Despite increased regulatory support for pediatric drug development, sponsors still face ethical, economic and practical constraints. Indeed, while children represent about 40% of the world’s population, only 10% of the drugs on the market have been approved for pediatrics.

Children are not small adults, and all children are not the same. In particular, children under the age of two are the most heterogeneous. They differ by maturation of organ development, drug metabolizing enzymes and transporters, protein binding, etc.

Neonates—babies from birth to the first month—are the least studied and most fragile pediatric population. In fact, fewer than 5% of pediatric drug trials include neonates. Within the neonatal population, there is a 10-fold difference in weight (0.5–5 kg) between extremely low birth weight preterm infants and full-term infants.

The lack of clinical studies in neonates has resulted in widespread off-label prescribing leading to under dosing, over dosing, and adverse events. A 2015 analysis in Clinical Pharmacology and Therapeutics by Gilbert J. Burckart, PharmD, and his FDA colleagues showed that a total of 44 products had failed pediatric drug development trials submitted to the FDA between 2007 and 2014. Under-dosing was a contributing factor to trial failures in 10 instances. Advances in physiologically-based pharmacokinetic (PBPK) modeling can help inform first-in-pediatric dosing and clinical study design.

The regulatory landscape for pediatric drug development

To address this urgent medical need, both the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) now require pediatric trial plans—the Pediatric Study Plan (PSP) and the Pediatric Investigation Plan (PIP), respectively—as part of the approval process for new drugs. In the FDA’s 2014 guidance on “General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products,” they recommend using modeling and simulation to reduce the uncertainty of dosing pediatric populations. PBPK has been increasingly used in pediatric drug development programs to help optimize pediatric study designs, especially in the 0-2 year old age group.

A brief introduction to PBPK modeling

PBPK models describe the behavior of drugs in the different body tissues. Depending on the route of administration, the course of the drug can be tracked through the blood and tissues. Each tissue is considered to be a physiological compartment. The concentration of the drug in each compartment is determined by combining systems data, drug data, and trial design information. The systems data includes demographic, physiological, and biochemical data for the individuals in the study population. The drug data consists of its physicochemical properties, its binding characteristics, and information on its metabolism and solubility. The trial design information comprises the dose, administration route, dosing schedule, and co-administered drugs.

Overview of the relationships between covariates affecting ADME

When building virtual human populations for ADME (absorption, distribution, metabolism, and excretion) simulation, the composition of the study group is considered with respect to age, sex, and ethnicity, plus genetic makeup of enzymes and transporter proteins in the target population. However, each factor influences multiple elements of ADME, creating non-linear and non-monotonic relationships. The sensitivity of each pharmacokinetic parameter to a potential covariate depends on the drug and the balance of sensitivities to elements within the network. As drugs differ in their sensitivity to these elements, covariates of pharmacokinetics vary and a “one-size-fits-all” solution cannot be assumed. Prior assessment of covariates ensures that the most relevant factors and the most suitable covariate models are considered during clinical studies.

PBPK modeling applications in pediatric oncology drug development

Childhood cancer represents more than 100 rare and ultra-rare diseases with an estimated 12,400 new cases diagnosed each year in the US. As such, this much smaller patient population presents unique challenges in pediatric oncology drug development. Developing drugs for pediatric malignancies also entails unique trial design considerations including flexible enrollment approaches, age appropriate formulations, acceptable sampling schedules, and balancing the need for age-stratified dosing regimens given the smaller patient populations. Several published examples in literature showed the successful application of PBPK to projecting the starting doses in various pediatric age groups, to optimizing the sampling scheme, sampling technique (e.g. dried blood spots), and calculating sample size. Increasing numbers of PBPK applications are being included in the submission package to support the PIP plan.


PBPK models have the potential to improve pediatric drug development. For children under two years of age, PBPK models can account for developmental changes in liver volume and blood flow, maturation of renal clearance, CYP/UGT ontogeny, and changes in drug absorption in the gut. For children over the age of two, PBPK approaches can help explain complex PK and support bridging formulations from adults to pediatrics. While progress has been made in developing pediatric PBPK models, they are still evolving, particularly for premature babies where some system parameters are “known unknowns.” Continued collaboration between academia, industry, and regulatory is critical for establishing best practices in using PBPK to support pediatric drug development.

To learn more, please watch a recent webinar that I gave on this topic.

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Alice Ke
Alice Ke obtained her PhD in pharmaceutics from the University of Washington, Seattle, where her research was focused on the assessment of fetal and CNS drug distribution using clinical imaging techniques. She then accepted an ORISE fellowship in the Office of Clinical Pharmacology at the FDA, where she developed and validated PBPK and population PK models to support dose adjustment for pregnant women. After completing her fellowship, Dr. Ke was a research scientist in the Department of Drug Disposition and PK/PD at Lilly Research Laboratories, where she applied population PK and PBPK modeling & simulation techniques to provide model-based advice on the design of clinical pharmacology studies. Currently, Dr. Alice Ke is a Consultant and Scientific Advisor at Simcyp. Her research interests continue to center around the applications of PBPK and PK/PD modeling to predicting complex drug interactions and PK/PD in special populations.