Scientific Publications by FDA Staff

Drug Metab Dispos 2016 Jul;44(7):924-33

Role of quantitative clinical pharmacology in pediatric approval and labeling.

Mehrotra N, Bhattaram A, Earp JC, Florian J, Krudys K, Lee JE, Lee JY, Liu J, Mulugeta Y, Yu J, Zhao P, Sinha V

Dose selection is one of the key decisions made during the 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 of the examples where pharmacometric analysis was utilized to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection is highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults while for adalimumab, exposure-response, PK, efficacy and safety data together was 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 the b.i.d. regimen, different q.d. dosing regimens for treatment-naive HIV-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 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 towards decisions pertaining to dose selection, trial designs and assessing disease similarity to adults to support extrapolation of efficacy.