Modeling and simulation in pediatric drug therapy: Application of pharmacometrics to define the right dose for children

Abstract

During the past decades significant progress has been made in our understanding of the importance of age-appropriate development of new drug therapies in children. Importantly, several regulatory initiatives in Europe and the US have provided a framework for a rationale. In the US, most notably the enactment of the Best Pharmaceuticals for Children Act (BPCA) and Product Research and Equity Act (PREA) has facilitated the studying of on-patent and off-patent drugs in children. The biggest challenge in pediatric studies is defining a safe and effective dose or dose range in a patient population that can span from premature neonates to adolescents. From a mechanism-based perspective, advances in the science of quantitative pharmacology and pharmacometrics have resulted in the development of model-based approaches to better describe and understand important age-related factors influencing drug disposition and response in pediatric patients. The application of modeling and simulation has been shown to result in better estimates of pediatric doses as evidenced by several studies, although the optimal approach is still being debated. The extrapolation of efficacy findings from adults to the pediatric population has streamlined the development process especially for studies in older children. However, a focus on developmental changes in neonates and infants as well as further developing a paradigm for conducting pharmacodynamic studies in neonates, infants, and children remain important unmet needs. In this overview we will review current approaches for age-appropriate dose selection and highlight ongoing efforts to define exposure-response and clinical outcome relationships across the pediatric age spectrum.

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling

“…Advances in the science of quantitative pharmacology and the use of model-based drug development have paralleled the advances in pediatric research (Stockmann et al, 2015;Vinks et al, 2015). The use of modeling and simulation (M&S) as an integral part of and basis for improving efficiency, substantiating trial design, and optimizing dose selection in pediatric drug development has been communicated in recent guidance (http://www.fda.gov/downloads/drugs/ guidancecomplianceregulatoryinformation/guidances/ucm425885.pdf).…”

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

“…However, clinicians continue to struggle with finding the right dose due to our incomplete understanding of the factors predicting the large variability in morphine pharmacokinetics (PKs) among patients. The variability in morphine disposition is considered to result from a combination of pharmacogenetic and physiological determinants, whereas in pediatric patients the age‐dependent developmental changes also need to be considered 1, 2. Application of physiologically‐based pharmacokinetic (PBPK) modeling is recognized as an informative approach to explore the combined effects of the system parameter3 (e.g., physiology and genetics) and drug parameters (e.g., physicochemical and in vitro PK properties).…”

Bridging Adult Experience to Pediatrics in Oncology Drug Development

“…29 Allometric scaling of drug clearance from adults to children based on body weight or body surface area and adjustment for organ function and maturation can be applied using population PK modeling to project pediatric doses that match the exposure of adult doses. 30,31 Several recent examples of model-informed pediatric dose selection leveraging adult clinical data are available. Dose selection for venetoclax in pediatric patients with acute myelogenous leukemia, acute lymphocytic leukemia, non-Hodgkin lymphoma, or neuroblastoma was based on matching exposures (area under the plasma concentration-time curve at steady state) in S133 pediatric patients to exposures associated with safety and efficacy in adult patients with chronic lymphocytic leukemia.…”