Fundamentals of Pediatric Drug Dosing

Fundamentals of Pediatric Drug Dosing

Gilbert Burckart Editors Fundamentals of Pediatric Drug Dosing

Editors Clinical Pharmacology/Biopharmaceutics Food & Drug Administration Silver Spring Maryland USA Gilbert Burckart Clinical Pharmacology Food & Drug Administration, Pediatric Group Silver Spring Maryland USA ISBN 978-3-319-43752-1 ISBN 978-3-319-43754-5 (ebook) DOI 10.1007/978-3-319-43754-5 Library of Congress Control Number: 2016956626 Springer International Publishing Switzerland 2016 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper This Adis imprint is published by Springer Nature The registered company is Springer International Publishing AG The registered company address is Gewerbestrasse 11, 6330 Cham, Switzerland

Preface The fundamentals of pediatric drug dosing are still evolving. While this may sound strange in the twenty-first century, it is a true statement. From 1950 to 1980, a sense of importance of understanding pediatric drug therapy came about, but the ability to apply scientific principles to pediatric drug dosing was impossible. While the science of pharmacokinetics and pharmacodynamics advanced from 1980 to 2000, few investigators attempted to apply these principles to pediatric dosing. From 2000 to the present, due to legislation in the USA and in Europe, we went from essentially zero to well over 1000 pediatric drug development trials that have been conducted and submitted to the US Food and Drug Administration. So many pediatric trials in such a short period of time led to inevitable failures, in some cases failure was due to a poor understanding of drug dosing. But the encouraging development is that we are learning at a rapid pace, and the full attention of many more scientists is now trained on the pediatric patient. The pediatric patient, who ranges from an extreme premature infant weighing 1.0 kg to an adolescent weighing 70 120 kg, presents a remarkable challenge in understanding the science of drug dosing. Therefore this book is very timely, and should provide both the student and the scholar with new information on a comprehensive list of topics required to properly understand pediatric drug dosing. With the regulatory changes that are described that will bring us drug development studies in newborns for the first time, new ground is continuing to be broken in the science of drug dosing and its application to pediatric patients. At the same time, I have to admit that we have a considerable amount to learn, and the next decade (or two!) will continue to bring us new models, new concepts, and perhaps best of all, better dosing of new drugs for the welfare of our pediatric patients. Silver Spring, MD, USA Gilbert J. Burckart v

Contents 1 Pediatric Drug Development and the Regulatory Changes That Are Creating the Science of Pediatric Dosing................. 1 Gilbert J. Burckart 2 Pediatric Physiology......................................... 13 3 Developmental Pharmacology: Impact on Pharmacokinetics and Pharmacodynamics of Drugs................................................... 23 4 Pediatric Clinical Trial Design and Dosing....................... 45 Dionna Green and Valerie Amspacher 5 Application of Allometric Principles in Pediatric Drug Development.......................................... 65 6 Population Pharmacokinetics in Pediatric Drug Development.......................................... 83 Jeremiah D. Momper, John Bradley, and Brookie M. Best 7 Scaling Dose-Exposure-Response from Adults to Children................................................. 93 Ine Skottheim Rusten, Anna Nordmark, Susan Cole, Joseph F. Standing, Sofia Friberg Hietala, Wei Zhao, Valeria Gigante, Anna Karin Hamberg, Gérard Pons, María Jesús Garrido, Johannes Taminiau, Norbert Benda, Frederike Lentz, Flora Musuamba Tshinanu, Andrew Thomson, Paolo Tomasi, Cecile Ollivier, Ralf Herold, and Efthymios Manolis vii

viii Contents 8 Applications of Physiologically Based Pharmacokinetic (PBPK) Models for Pediatric Populations............................. 109 Peng Duan, Jeffrey Fisher, and Jian Wang 9 Perinatal Pharmacology and Maternal/Fetal Dosing............. 127, Gilbert J. Burckart and Robert M. Ward