title: Exposure Matching for Extrapolation of Efficacy in Pediatric Drug Development.
abstract: During drug development, matching adult systemic exposures of drugs is a common approach for dose selection in pediatric patients when efficacy is partially or fully extrapolated. This is a systematic review of approaches used for matching adult systemic exposures as the basis for dose selection in pediatric trials submitted to the US Food and Drug Administration (FDA) between 1998 and 2012. The trial design of pediatric pharmacokinetic (PK) studies and the pediatric and adult systemic exposure data were obtained from FDA publicly available databases containing reviews of pediatric trials. Exposure-matching approaches that were used as the basis for pediatric dose selection were reviewed. The PK data from the adult and pediatric populations were used to quantify exposure agreement between the 2 patient populations. The main measures were the pediatric PK studies' trial design elements and drug systemic exposures (adult and pediatric). There were 31 products (86 trials) with full or partial extrapolation of efficacy with an available PK assessment. Pediatric exposures had a range of mean Cmaxand AUC ratios (pediatric/adult) of 0.63 to 4.19 and 0.36 to 3.60, respectively. Seven of the 86 trials (8.1%) had a predefined acceptance boundary used to match adult exposures. The key PK parameter was consistently predefined for antiviral and anti-infective products. Approaches to match exposure in children and adults varied across products. A consistent approach for systemic exposure matching and evaluating pediatric PK studies is needed to guide future pediatric trials.
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Yeruk
authors.initials: Y
authors.lastname: Mulugeta
authors.affiliation: Division of Clinical Pharmacology & Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Barrett
authors.affiliation: Office of Pediatric Therapeutics, Office of the Commissioner, US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Nelson
authors.affiliation: Office of Biostatistics, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Abel Tilahun
authors.initials: AT
authors.lastname: Eshete
authors.affiliation: Children's National Medical Center, Washington, DC, USA.
authors.forename: Alvina
authors.initials: A
authors.lastname: Mushtaq
authors.affiliation: Pediatric and Maternal Health Staff, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Lynne
authors.initials: L
authors.lastname: Yao
authors.affiliation: University of Maryland School of Pharmacy, Baltimore, MD, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Glasgow
authors.affiliation: Division of Gastroenterology and Inborn Errors Products, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Mulberg
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonzalez
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Dionna
authors.initials: D
authors.lastname: Green
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Jeffry
authors.initials: J
authors.lastname: Florian
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Krudys
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Shirley
authors.initials: S
authors.lastname: Seo
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Insook
authors.initials: I
authors.lastname: Kim
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Dakshina
authors.initials: D
authors.lastname: Chilukuri
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA. gilbert.burckart@fda.hhs.gov.
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Burckart
mesh_terms: D000328:Adult; D000367:Age Factors; D002648:Child; D002986:Clinical Trials as Topic / Q000379:methods; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods* / Q000639:trends; D006801:Humans; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism; D016896:Treatment Outcome; D014481:United States; D014486:United States Food and Drug Administration / Q000639:trends
chemical_list: D004364:Pharmaceutical Preparations
keywords: dosing; drug development; exposure matching; extrapolation; pediatrics