title: 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 twice-daily regimen, different once-daily dosing regimens for treatment-naïve 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.
authors.affiliation: 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.
authors.forename: Nitin
authors.initials: N
authors.lastname: Mehrotra
authors.affiliation: 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.
authors.forename: Atul
authors.initials: A
authors.lastname: Bhattaram
authors.affiliation: 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.
authors.forename: Justin C
authors.initials: JC
authors.lastname: Earp
authors.affiliation: 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.
authors.forename: Jeffry
authors.initials: J
authors.lastname: Florian
authors.affiliation: 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.
authors.forename: Kevin
authors.initials: K
authors.lastname: Krudys
authors.affiliation: 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.
authors.forename: Jee Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Joo Yeon
authors.initials: JY
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Yeruk
authors.initials: Y
authors.lastname: Mulugeta
authors.affiliation: 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.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Vikram
authors.initials: V
authors.lastname: Sinha
mesh_terms: D000068879:Adalimumab / Q000008:administration & dosage / Q000493:pharmacokinetics; D000293:Adolescent; D041923:Adolescent Development; D000328:Adult; D000367:Age Factors; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics; D002648:Child; D002657:Child Development; D002675:Child, Preschool; D003424:Crohn Disease / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D017277:Drug Approval; D054796:Drug Dosage Calculations; D004348:Drug Labeling; D064098:Esomeprazole / Q000008:administration & dosage / Q000493:pharmacokinetics; D005764:Gastroesophageal Reflux / Q000188:drug therapy; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism*; D010599:Pharmacokinetics; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D012640:Seizures / Q000188:drug therapy; D020888:Vigabatrin / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D019380:Anti-HIV Agents; D000893:Anti-Inflammatory Agents; D000927:Anticonvulsants; D004364:Pharmaceutical Preparations; D054328:Proton Pump Inhibitors; D000068879:Adalimumab; D020888:Vigabatrin; D064098:Esomeprazole