Nonclinical assessment of abuse potential for new pharmaceuticals

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Nonclinical Assessment of ABUSE POTENTIAL FOR NEW PHARMACEUTICALS Edited by CARRIE G MARKGRAF THOMAS J HUDZIK DAVID R COMPTON Amsterdam • Boston • Heidelberg • London New York • Oxford • Paris • San Diego San Francisco • Singapore • Sydney • Tokyo Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 225 Wyman Street, Waltham, MA 02451, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright © 2015 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein ISBN: 978-0-12-420172-9 British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress For information on all Academic Press publications visit our website at Publisher: Mica Haley Acquisition Editor: Kristine Jones Editorial Project Manager: Molly McLaughlin Production Project Manager: Lucia Perez Designer: Matthew Limbert Typeset by TNQ Books and Journals CONTRIBUTORS Theodore J Baird Toxicology, Medivation Inc., San Francisco, CA, USA Matthew L Banks Department of Pharmacology and Toxicology, Medical College of Virginia, Richmond,VA, USA Michael T Bardo Department of Psychology and Center for Drug Abuse Research Translation, University of Kentucky, Lexington, KY, USA Patrick M Beardsley Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA Anton Y Bespalov Laboratory of Behavioral Pharmacology, Institute of Pharmacology, Pavlov Medical University, St Petersburg, Russia August R Buchhalter PinneyAssociates, Bethesda, MD, USA Silvia Calderon Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA David R Compton Preclinical Safety, Sanofi US, Bridgewater, NJ, USA; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond,VA, USA Edward J Cone PinneyAssociates, Bethesda, MD, USA Paul W Czoty Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston–Salem, NC, USA Michelle D Ertischek PinneyAssociates, Bethesda, MD, USA Reginald V Fant PinneyAssociates, Bethesda, MD, USA Charles P France Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA David V Gauvin Neurobehavioral Sciences, MPI Research Inc., Mattawan, MI, USA Karen K Gerlach PinneyAssociates, Bethesda, MD, USA ix x Contributors Alessandra Giarola Safety Pharmacology Department, GlaxoSmithKline, Ware, Hertfordshire, UK Mausumee Guha Medivation Inc., San Francisco, CA, USA David Heal RenaSci Ltd., BioCity, Nottingham, UK Jack E Henningfield PinneyAssociates, Bethesda, MD, USA; School of Medicine, Johns Hopkins University, ­Baltimore, MD, USA David B Horton Global Safety Pharmacology, Drug Safety Research and Development, Pfizer Research and Development, Groton, CT, USA Thomas J Hudzik Development Sciences, Preclinical Safety, AbbVie Ltd., N Chicago, IL, USA Mary Jeanne Kallman Preclinical Neuroscience, Covance Laboratories, Lead Optimization, Greenfield, IN, USA Carrie G Markgraf Discovery Sciences Support, Merck and Co Ltd., Kenilworth, NJ, USA Michael A Nader Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston–Salem, NC, USA Sidney H Schnoll PinneyAssociates, Bethesda, MD, USA Marta Sokolowska Grünenthal USA Inc., Bedminster, NJ, USA Michael D.B Swedberg Swedberg Preclinical Partner AB (Inc.), Trosa, Sweden Greet Teuns Janssen R&D,    Janssen Pharmaceutica NV, Beerse, Belgium Mark S Todtenkopf Life Sciences and Toxicology Department, Alkermes, Inc., Waltham, MA, USA Suzanne K Vosburg Grünenthal USA Inc., Bedminster, NJ, USA Justin R Yates Department of Psychology and Center for Drug Abuse Research Translation, University of Kentucky, Lexington, KY, USA; Department of Psychological Science, Northern Kentucky University, Highland Heights, KY, USA FOREWORD The epidemic of drug abuse has been studied and written about extensively for the past few decades According to the Centers for Disease Control and Prevention (CDC)1, drug overdose death rates in the United States more than tripled from 1990 to 2008 Overdose deaths involving opioid analgesics increased and exceeded deaths involving heroin and cocaine combined The CDC analyzed rates of fatal overdoses, nonmedical use, sales, and treatment admissions for opioid analgesics In 2008, drug overdoses in the United States caused 36,450 deaths Opioids were involved in 14,800 deaths (73.8%) of the 20,044 prescription drug overdose deaths Most abuse involves polypharmacy whereby abuse involves the use of opioids in combination with other central nervous system-active drugs for enhanced effects or for otherwise altering the pharmacologic effect During 1999–2008, overdose death rates, sales, and substance abuse treatment admissions related to opioids all increased substantially Other statistics describe the issue with details about regions of the country that are particularly affected by the current national drug abuse problem Each manner in which data on abuse is presented makes the problem seem closer to all of us and more and more personal Individual stories are routinely reported in newspapers about seemingly average people, including young people, who are affected by the availability of prescription and nonprescription drugs with abuse potential In some cases, they are being treated with a medicine and begin abusing it, and then they take it for recreational purposes and become dependent Such use may lead to addiction and overdose and, in the worst cases, death The abuse potential of a new drug needs to be assessed in controlled nonclinical and clinical studies before it is approved for marketing The general public wants to know about the drugs that they take and they want to be informed about their risks and likelihood for abuse before they become a problem Drug developers and regulators need to acquire this information as early as possible Many types of prescription drugs are abused (opioids, sedatives, hypnotics, stimulants, and hallucinogens) and abuse in the US is primarily in the form of polypharmacy.These drug classes comprise most substances that are listed in the schedules of the Controlled Substances Act (CSA)2 A single drug for abuse appears to be an infrequent event, though confirmatory and specific data describing an abuse incident is not often available In 2011, the Drug Abuse Warning Network (DAWN)3 ceased to collect data related to actual drug abuse encounters reported in 1Morb Mortal Wkly Rep 2011 Nov 4; 60(43):1487–92.Vital signs: overdoses of prescription opioid pain relievers– United States, 1999–2008 2Title 21 Food and Drugs Chapter 13: Drug Abuse Prevention and Control 3 xi xii Foreword hospital emergency departments and medical examiners A compilation of DAWN reports once provided annual national statistics on abuse, often of specific drug products and the combinations of drugs that are abused Since 2011, a greater reliance on this type of information has fallen to a variety of surveys and other sources of data, including poison control center reports to identify drug abuse problems Oftentimes, abuse and diversion data are not systematically acquired and the reliability of such data is questioned These sorts of data also cannot be trended from year to year, so they not allow us to interpret with accuracy the meaning of any observed annual changes in patterns of use, extent of drug use, and new drug abuse fads Determining whether things are getting better or whether regulatory efforts are successful is difficult if one relies on such data.We are limited in our ability to know whether new approaches have been successful and where future efforts should be applied when successes are based on data that are not systematically collected Anticipated problems and needed risk management can be predicted by the assessment of the drug’s abuse potential Rigorous scientific studies and a logical approach to conducting studies on the abuse potential of drugs are needed prior to approval and marketing Drug regulators can make a risk benefit calculation of the drug and ensure that appropriate risk management strategies are in place to address anticipated problems Several years ago, I was told by a pharmaceutical industry representative that the abuse potential assessment of a drug is arcane—a mysterious and obscure process known only to a few To him and many others, assessing the abuse potential of a drug seemed to rely more on anecdotal reports of abuse than on scientific data and analysis One inherent problem with the assessment of abuse potential was that it relied on a random consensus of nonclinical and clinical interdisciplinary scientific data from a variety of studies The sort of studies and the Food and Drug Administration (FDA) standards and expectations from these studies were not widely known.The investment of capital (intellectual and otherwise) into conducting these studies and developing an abuse potential assessment and integrating it into the entire drug development process was largely unheard of Such efforts needed to be justified and directed such that not only were meaningful scientific results produced but that the appropriate studies were performed at the appropriate times and on a fair playing field for all companies Companies were limited in their ability to perform a successful program in this area prior to the FDA publication of the draft Guidance for Industry: Assessment of Abuse Potential of Drugs4 in January 2010 The Guidance provided a framework for assessing abuse potential In addition to describing the types of studies and data that are needed, the Guidance laid out a stepwise scientific approach, offering a logical sequence and timeline for performing certain studies before others, whereby later studies could build on results from earlier 4 (Published January 27, 2010) Foreword studies as new information about the new drug is obtained Today, the assessment of abuse potential is a part of the FDA’s Twenty-First Century Drug Review Process in the Center for Drug Evaluation and Research (FDA/CDER) For drugs with abuse potential, expert regulatory reviewers participate in all milestone meetings and prepare reviews of the studies with recommendations prior to approval The assessment of the abuse potential of a drug—whether new or well-known and already on the market—is part of the evaluation of the overall safety profile of a drug.The safety profile evaluation for a drug relates to the medical use of a drug and is primarily applicable to patient populations In this context, the risk benefit determination for the drug can be made, since all drugs offer risks and potential therapeutic benefits A unique feature of a drug’s abuse potential is that the “abuse” of a drug affects a wider population of individuals than patients Different populations are affected (or at risk) and studies in different populations often show a range of effects to the drug For this reason, the pivotal human abuse potential study is carried out in experienced or recreational drug abusers, rather than drug-naïve healthy subjects or patient populations who are prescribed a drug for intended therapeutic purposes When a company submits a new drug application (NDA) to the FDA for review and approval, if the drug has a potential for abuse, the company must submit in the NDA an analysis of studies and other information related to the potential abuse and dependence liability of the drug and propose scheduling under the CSA, if appropriate, and drug product labeling that is supported by study data The company project management should ensure that the drug development process addresses all pertinent nonclinical and clinical study data related to biochemistry, pharmacology, animal behavior and dependence, pharmacokinetics, chemistry, and drug formulation An adverse events profile that includes events such as euphoria and hallucinations that are related to abuse potential are relevant The nonclinical data informs us early in development of the likely mechanism of action of the drug and is highly predictive of how the drug should be studied further in humans The early safety pharmacology and in vitro binding studies are useful in informing us about the drug’s possible central nervous system activity and similarity to other known drugs of abuse We gain from these studies an understanding of the relationship of the drug’s pharmacology to neurotransmitters that may be associated with the mechanism of action leading to abuse Importantly, the nonclinical studies are useful in the design of other behaviorally related animal studies (such as the drug discrimination and self-administration paradigms) in the selection of appropriate positive controls and doses Importantly, the nonclinical study results assist in designing human abuse potential studies and provide assurance of safety in the conduct of clinical studies so that the necessary safeguards are in place at the start of the clinical studies A thorough knowledge of the nonclinical data of the new drug assists in interpreting adverse events related to abuse that are reported in Phase of development and postmarketing as well xiii xiv Foreword This book presents numerous contributions on the nonclinical assessment of abuse potential for new pharmaceuticals by expert scientists from industry, academia, and government It contains a wide range of information on scientific laboratory studies that are used in acquiring data on drug abuse for new drugs Finally, the book contains vital information beneficial to pharmaceutical companies, researchers, policymakers, and all others who are engaged in areas of drug development and drug abuse issues Michael Klein, PhD5 Director Controlled Substance Staff The opinions and information in this presentation are those of the author and not necessarily reflect the views and policies of the FDA PREFACE As undergraduate and then graduate students, many can recall being captivated by the idea, presented by B.F Skinner and others, that animal behavior could represent, with high fidelity, the behavior of humans The early work of Peter Dews showed us that the operant behavior of pigeons, responding under a particular schedule of reinforcement, provided a baseline from which to assess the adaptation of the organism to the schedule, as well as a stable baseline to understand the effects of drugs The measured behaviors, as well as drug responses, were remarkably conserved across all species, up to and including humans This growing field of behavioral pharmacology was quickly adapted to the study of drugs of abuse, and along with it came the revelation that any given animal would engage in behavior that resulted in administration of drugs of abuse, the topic of some seminal reviews That drugs could be seen as reinforcers of behavior, and that many behaviors were conserved among species caused a shift in thinking about drug addiction from some type of character flaw or moral weakness to a pathophysiological continuum from normal, biologically typical (and acceptable) seeking behaviors to abnormal, atypical (and unacceptable) behavior(s) resulting from over-activation of reward pathways in brain pathways highly conserved across species; just as animal behavioral responses occurring under schedules of positive reinforcement As a result, models of abuse potential covered in this volume are among the most predictive to humans of all animal models However, the current challenge is that industry and regulatory scientists need to learn how to apply these well-described and long-established models to a new purpose: to profile the potential for abuse of new pharmaceuticals and, where possible, to mitigate the potential negative human health consequences of medication misuse and/or abuse The focus of this book is to review current knowledge of the state of these models from the perspective, when possible, of pharmaceutical drug development and to demonstrate how the models are applicable to this problem presented by novel chemical entities Carrie Markgraf, PhD Thomas Hudzik, PhD David Compton, PhD xv ACKNOWLEDGMENTS We would like to thank Mark Ammann (and the CCALC), without whom we would not have started on this particular adventure We would also like to acknowledge our professors, advisors, and colleagues who have inspired and guided us along our career paths toward improving human health and safety, notably from DRC: Kenneth M Johnson, and collaborator, mentor, and dear friend Billy R Martin (deceased); from TH: George Wagner, John Falk, Don McMillan, Galen Wenger, Bob Balster and Bob Schuster; and from CGM: Bob Osborne and Bruce Kapp A special thank you also to Mary Jeanne Kallman: a colleague, friend, and inspiration to so many xvii ... drug’s actual or relative potential for abuse; scientific evidence of its pharmacological effects; Nonclinical Assessment of Abuse Potential for New Pharmaceuticals the state of current scientific... 89–101 15 16 Nonclinical Assessment of Abuse Potential for New Pharmaceuticals Table 4  Drug Classes of Concern with Abused/Scheduled Representative Examples A listing of both drug classes of concern... a set of behaviors leading to the repeated, excessive self-administration of a substance, despite the resultant appearance of negative Nonclinical Assessment of Abuse Potential for New Pharmaceuticals
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