PMID- 27079249 OWN - NLM STAT- MEDLINE DCOM- 20180123 LR - 20180323 IS - 1521-009X (Electronic) IS - 0090-9556 (Linking) VI - 44 IP - 7 DP - 2016 Jul TI - Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling. PG - 924-33 LID - 10.1124/dmd.116.069559 [doi] AB - 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 twice-daily regimen, different once-daily dosing regimens for treatment-naive 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. CI - Copyright (c) 2016 U.S. Government work not protected by U.S. copyright. FAU - Mehrotra, Nitin AU - Mehrotra N AD - Division of Pharmacometrics, Office of Clinical Pharmacology (N.M., A.B., J.C.E., J.F., K.K., J.E.L., J.L., Y.M., J.Y., P.Z., V.S.), and Division of Biometrics VII, Office of Biostatistics (J.Y.L.), Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland nitin.mehrotra@fda.hhs.gov. FAU - Bhattaram, Atul AU - Bhattaram A AD - Division of Pharmacometrics, Office of Clinical Pharmacology (N.M., A.B., J.C.E., J.F., K.K., J.E.L., J.L., Y.M., J.Y., P.Z., V.S.), and Division of Biometrics VII, Office of Biostatistics (J.Y.L.), Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. FAU - Earp, Justin C AU - Earp JC AD - Division of Pharmacometrics, Office of Clinical Pharmacology (N.M., A.B., J.C.E., J.F., K.K., J.E.L., J.L., Y.M., J.Y., P.Z., V.S.), and Division of Biometrics VII, Office of Biostatistics (J.Y.L.), Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. FAU - Florian, Jeffry AU - Florian J AD - Division of Pharmacometrics, Office of Clinical Pharmacology (N.M., A.B., J.C.E., J.F., K.K., J.E.L., J.L., Y.M., J.Y., P.Z., V.S.), and Division of Biometrics VII, Office of Biostatistics (J.Y.L.), Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. FAU - Krudys, Kevin AU - Krudys K AD - Division of Pharmacometrics, Office of Clinical Pharmacology (N.M., A.B., J.C.E., J.F., K.K., J.E.L., J.L., Y.M., J.Y., P.Z., V.S.), and Division of Biometrics VII, Office of Biostatistics (J.Y.L.), Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. FAU - Lee, Jee Eun AU - Lee JE AD - Division of Pharmacometrics, Office of Clinical Pharmacology (N.M., A.B., J.C.E., J.F., K.K., J.E.L., J.L., Y.M., J.Y., P.Z., V.S.), and Division of Biometrics VII, Office of Biostatistics (J.Y.L.), Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. FAU - Lee, Joo Yeon AU - Lee JY AD - Division of Pharmacometrics, Office of Clinical Pharmacology (N.M., A.B., J.C.E., J.F., K.K., J.E.L., J.L., Y.M., J.Y., P.Z., V.S.), and Division of Biometrics VII, Office of Biostatistics (J.Y.L.), Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. FAU - Liu, Jiang AU - Liu J AD - Division of Pharmacometrics, Office of Clinical Pharmacology (N.M., A.B., J.C.E., J.F., K.K., J.E.L., J.L., Y.M., J.Y., P.Z., V.S.), and Division of Biometrics VII, Office of Biostatistics (J.Y.L.), Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. FAU - Mulugeta, Yeruk AU - Mulugeta Y AD - Division of Pharmacometrics, Office of Clinical Pharmacology (N.M., A.B., J.C.E., J.F., K.K., J.E.L., J.L., Y.M., J.Y., P.Z., V.S.), and Division of Biometrics VII, Office of Biostatistics (J.Y.L.), Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. FAU - Yu, Jingyu AU - Yu J AD - Division of Pharmacometrics, Office of Clinical Pharmacology (N.M., A.B., J.C.E., J.F., K.K., J.E.L., J.L., Y.M., J.Y., P.Z., V.S.), and Division of Biometrics VII, Office of Biostatistics (J.Y.L.), Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. FAU - Zhao, Ping AU - Zhao P AD - Division of Pharmacometrics, Office of Clinical Pharmacology (N.M., A.B., J.C.E., J.F., K.K., J.E.L., J.L., Y.M., J.Y., P.Z., V.S.), and Division of Biometrics VII, Office of Biostatistics (J.Y.L.), Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. FAU - Sinha, Vikram AU - Sinha V AD - Division of Pharmacometrics, Office of Clinical Pharmacology (N.M., A.B., J.C.E., J.F., K.K., J.E.L., J.L., Y.M., J.Y., P.Z., V.S.), and Division of Biometrics VII, Office of Biostatistics (J.Y.L.), Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. LA - eng PT - Journal Article PT - Review DEP - 20160414 PL - United States TA - Drug Metab Dispos JT - Drug metabolism and disposition: the biological fate of chemicals JID - 9421550 RN - 0 (Anti-HIV Agents) RN - 0 (Anti-Inflammatory Agents) RN - 0 (Anticonvulsants) RN - 0 (Pharmaceutical Preparations) RN - 0 (Proton Pump Inhibitors) RN - FYS6T7F842 (Adalimumab) RN - GR120KRT6K (Vigabatrin) RN - N3PA6559FT (Esomeprazole) RN - Pediatric Crohn's disease SB - IM MH - Adalimumab/administration & dosage/pharmacokinetics MH - Adolescent MH - Adolescent Development MH - Adult MH - Age Factors MH - Anti-HIV Agents/administration & dosage/pharmacokinetics MH - Anti-Inflammatory Agents/administration & dosage/pharmacokinetics MH - Anticonvulsants/administration & dosage/pharmacokinetics MH - Child MH - Child Development MH - Child, Preschool MH - Crohn Disease/drug therapy MH - Dose-Response Relationship, Drug MH - *Drug Approval MH - *Drug Dosage Calculations MH - *Drug Labeling MH - Esomeprazole/administration & dosage/pharmacokinetics MH - Gastroesophageal Reflux/drug therapy MH - HIV Infections/drug therapy MH - Humans MH - Infant MH - Infant, Newborn MH - Models, Biological MH - Pharmaceutical Preparations/*administration & dosage/*metabolism MH - *Pharmacokinetics MH - Proton Pump Inhibitors/administration & dosage/pharmacokinetics MH - Seizures/drug therapy MH - Vigabatrin/administration & dosage/pharmacokinetics EDAT- 2016/04/16 06:00 MHDA- 2018/01/24 06:00 CRDT- 2016/04/16 06:00 PHST- 2016/01/15 00:00 [received] PHST- 2016/04/13 00:00 [accepted] PHST- 2016/04/16 06:00 [entrez] PHST- 2016/04/16 06:00 [pubmed] PHST- 2018/01/24 06:00 [medline] AID - dmd.116.069559 [pii] AID - 10.1124/dmd.116.069559 [doi] PST - ppublish SO - Drug Metab Dispos. 2016 Jul;44(7):924-33. doi: 10.1124/dmd.116.069559. Epub 2016 Apr 14.