Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling

Abstract

Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twicedaily regimen, different once-daily dosing regimens for treatmentnaïve human immunodeficiency virus 1-infected pediatric subjects 3 to <12 years of age were evaluated. The role of physiologically based pharmacokinetic modeling (PBPK) in predicting pediatric PK is rapidly evolving. However, regulatory review experiences and an understanding of the state of science indicate that there is a lack of established predictive performance of PBPK in pediatric PK prediction. Moving forward, pharmacometrics will continue to play a key role in pediatric drug development contributing toward decisions pertaining to dose selection, trial designs, and assessing disease similarity to adults to support extrapolation of efficacy.

Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children

“…Collectively, these innovations demonstrate that PBPK modeling is a powerful tool that can play a significant role in optimizing pediatric dosing, supporting drug approval, and ensuring that clinically relevant drug concentrations are achieved at the appropriate site of action. Despite significant potential, however, PBPK modeling in pediatric submissions to the FDA is uncommon, comprising only 17% of records between 2008 and 2015 . This is likely due to uncertainty regarding the ontogeny of many pediatric PK processes, including drug‐metabolizing enzymes and drug transporters .…”

Drug Dosing in Pregnant Women: Challenges and Opportunities in Using Physiologically Based Pharmacokinetic Modeling and Simulations

“…In these applications, PBPK modeling is primarily used to facilitate the decision making process on whether, when, and how to conduct a clinical pharmacology study, and, more importantly, to inform drug labeling to support dosing recommendations . Increasingly, the regulatory incentives and challenges in conducting and obtaining clinical data in special populations have significantly contributed to the increased use of PBPK models in pediatric and organ impairment populations …”

Development of Drug Therapies for Newborns and Children

“…The experience with the use of model-based analysis to support regulatory decisions in pediatric drug development has been previously described and includes optimization of dose selection; substantiation of trial design; and description of dose–exposure and exposure–response relationships to support extrapolation of efficacy from adult data. 17–19 …”

“…17 During this time, prescribers are forced to use products off-label in their pediatric patients. Many studies have shown that off-label drug use in pediatrics is associated with significantly increased risk for developing adverse drug reactions.…”