Pharmaceutical Product Development In Vitro-In VivoCorrelation edited by Dakshina Murthy Chilukuri U.S. Food and Drug Administration (FDA) Silver Spring, Maryland, U.S.A. Gangadhar Sunkara Novartis Pharmaceuticals East Hanover, New Jersey, U.S.A. David Young AGI Therapeutics, Inc. Columbia, Maryland, U.S.A. New York London Informa Healthcare USA, Inc. 270 Madison Avenue New York, NY 10016 © 2007 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8493-3827-1 (Hardcover) International Standard Book Number-13: 978-0-8493-3827-4 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. 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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Pharmaceutical product development / edited by Dakshina Murthy Chilukuri, Gangadhar Sunkara, David Young. p. ; cm. -- (Drugs and the pharmaceutical sciences ; v. 165) Includes bibliographical references and index. ISBN-13: 978-0-8493-3827-4 (hardcover : alk. paper) ISBN-10: 0-8493-3827-1 (hardcover : alk. paper) 1. Drug development. 2. Drugs--Design. I. Chilukuri, Dakshina Murthy. II. Sunkara, Gangadhar. III. Young, David, 1952- IV. Series. [DNLM: 1. Drug Design. 2. Biological Availability. 3. Drug Evaluation, Preclinical--methods. W1 DR893B v.165 2007 / QV 744 P5348 2007] RM301.25.P395 2007 615’.1--dc22 2006050423 Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com To my mother, Chilukuri Shyamalamba, my (late) father, Chilukuri RamachandraMurthy, and my wife, Ishwarya. Dakshina Murthy Chilukuri Idedicate thisbook to my father, Sri Prakasa Rao, mother, Smt Ammajamma,wife, Nagalakshmi,and son, Kiran Sai, for theirloving supportand caring. Gangadhar Sunkara Dedicated to my parents, Jack and Grace, my wonderfulwife, Karen, and my twofantastic children, Bethany and Kyle. David Young Preface Thedevelopmentofanewdrugfromthelaboratorytothepatienttakesbetween 10 to 15 years and costs hundreds of millions of dollars. The pharmaceutical industry,inconjunctionwiththeregulatorybodiesacrosstheworld,hascontinu- ouslysoughttoreducethetimetobringanewdrugtothemarketandreducethe cost of drug development in order to maximize return on the investment and to bring drugs to patients sooner. In the last two decades, the pharmaceutical industry has experimented with and successfully adopted several integrated and multidisciplinary approaches to achieve these reductions in development efforts. These efforts were primarily made in the research areas of drug compound screening, toxicological evaluation, and pharmaceutical product development. Owingtothescientificadvancesinthedevelopmentofchemicallycomplex therapeutic agents (e.g., recombinant proteins/peptides, gene-based drugs) intended for chronic therapies, there is a growing need for the continuous development of suitable formulation either as conventional immediate release oral formulation or controlled and/or continuous delivery via oral or parenteral routes. As formulation and delivery strategies can enhance competitive advan- tage for pharmaceutical companies, several chemical- and formulation-related issues are driving the early- and late-stage development of drug products. In the last few decades, significant medical advances have been made in the area of drug delivery with the development of novel dosage forms. However, the delivery of several classes of drugs continues to be a challenge, mainly due to shortbiologicalhalf-lives,poormembranepermeability,andassociatedtoxicity in the administered doses. Since more is now known about the relationship betweenchemicalproperties and movement of drugs throughout the body, drug discovery scientists are able to consider the pharmacokinetic properties of agents much earlier in the drug/product development process. Formulationdevelopmentconnectsseveralkeypreclinicalandclinicaltrials to support the new drug application. Formulation development and optimization involves varying excipient levels,processing methods, identifying discriminating dissolutionmethods,andsubsequentscale-upofthefinalproduct.Thequantitative andqualitativechangesinaformulationmayalterdrugreleaseandinvivoperform- ance.Developingapharmaceuticalproductformulationinatimelymanner,while v vi Preface ensuring quality, is a complex process that requires a systematic, science-based approach. Thus, ever increasing pressures to reduce pharmaceutical product developmenttimelineshaveresultedinpharmaceuticalscientistsinphysicalphar- macy, pharmaceutics, and pharmacology working collaboratively to develop an integrated approach of product development by addressing physicochemical and biological issues early on. Such continuous collaborative effort has resulted in thedevelopmentofanimportanttool:invitro–invivocorrelation. It is expected that the readers of this book possess a basic knowledge of biopharmaceutics and pharmacokinetics. The material presented in this text serves the need of scientists who are keen on utilizing the principles of in vitro–in vivo correlation in drug development. The objectives of this book are three-fold: i) to serve as a useful tool to help guide scientists in research and development by outlining the theory and successful practice of in vitro– in vivo correlation, ii) to help formulators apply the tool in designing and developing prototypes that enable selection of clinical formulations, and iii) to help formulate strategy(ies) for product life-cycle management. We would like to express our gratitude to the committed subject experts who have graciously agreed to spend their valuable time in writing the various chapters. Additional thanks to the publishers who have been supportive and considerate in an effort to bring out the best book possible. Dakshina Murthy Chilukuri GangadharSunkara David Young Contents Preface .... v Contributors .... ix 1. Dissolution:Fundamentals of In Vitro Release and the Biopharmaceutics Classification System ................ .. 1 Kevin C.Johnson 2. Pharmacokinetics: Basics of Drug Absorption from a Biopharmaceutical Perspective ....... .................. . 29 Sandhya K.Apparaju and Srikanth C. Nallani 3. Approachesto Developing InVitro–In Vivo Correlation Models ................. .................. . 47 Adrian Dunne 4. The Roleof In Vitro–In Vivo Correlation in Product Development and Life Cycle Management ................. . 71 Shoufeng Li, MartinMueller-Zsigmondy,andHequnYin 5. In Vitro–InVivo Correlation ......... .................. 107 Nishit B.Modi 6. IVIVC for Oral Drug Delivery: Immediate Release and Extended Release DosageForms ............... .................. 125 Colm Farrell andSiobhan Hayes 7. In Vitro–InVivo Correlation for ModifiedRelease Parenteral Drug Delivery Systems ..... .................. 141 David Young vii viii Contents 8. In Vitro–InVivo Correlation: TransdermalDrug Delivery Systems . .................. .................. 153 Ayyappa Chaturvedula andAjay K.Banga 9. In Vitro–InVivo Correlation: A Regulatory Perspective with Case Studies .................. .................. 177 Patrick J. Marroum Index .... 197 Contributors Sandhya K. Apparaju Food and Drug Administration, Silver Spring, Maryland, U.S.A. AjayK.Banga CollegeofPharmacy,MercerUniversity,Atlanta,Georgia, U.S.A. AyyappaChaturvedula GlaxoSmithKline,Parsippany,NewJersey,U.S.A. Adrian Dunne Schoolof Mathematical Sciences, University College Dublin, Dublin, Ireland ColmFarrell Department of Pharmacokinetics and Biopharmaceutics, GloboMax—ICONDevelopment Solutions, Marlow, Bucks, U.K. Siobhan Hayes Department of Pharmacokinetics and Biopharmaceutics, GloboMax—ICONDevelopment Solutions, Marlow, Bucks, U.K. Kevin C. Johnson Intellipharm, LLC, Niantic, Connecticut, U.S.A. Shoufeng Li Pharmaceuticaland Analytical Development,Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, U.S.A. Patrick J. Marroum Office of Clinical Pharmacology and Biopharmaceutics,Center for Drug EvaluationandResearch, Food andDrug Administration, Silver Spring, Maryland, U.S.A. NishitB.Modi DepartmentofClinical Pharmacology, ALZA Corporation, Mountain View, California, U.S.A. Martin Mueller-Zsigmondy Pharmaceutical andAnalytical Development, Novartis PharmaceuticalsAG, Basel, Switzerland ix