PHARMACOMETRICS THE SCIENCE OF QUANTITATIVE PHARMACOLOGY Edited by Ene I. Ette Anoixis Corporation Paul J. Williams University of the Pacifi c and Anoixis Corporation A JOHN WILEY & SONS, INC., PUBLICATION PHARMACOMETRICS PHARMACOMETRICS THE SCIENCE OF QUANTITATIVE PHARMACOLOGY Edited by Ene I. Ette Anoixis Corporation Paul J. Williams University of the Pacifi c and Anoixis Corporation A JOHN WILEY & SONS, INC., PUBLICATION Copyright © 2007 by John Wiley & Sons, Inc. All rights reserved. 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For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at 877-762-2974, outside the United States at 317-572-3993 or fax 317-572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com. Wiley Bicentennial Logo: Richard J. Pacifi co Library of Congress Cataloging-in-Publication Data: Pharmacometrics : the science of quantitative pharmacology / [edited by] Ene I. Ette, Paul J. Williams. p. ; cm. Includes bibliographical references. ISBN 978-0-471-67783-3 1. Pharmacology. 2. Pharmacokinetics. I. Ette, Ene I. II. Williams, Paul J. [DNLM: 1. Chemistry, Pharmaceutical–methods. 2. Drug Evaluation–methods. 3. Models, Theoretical. 4. Pharmacoepidemiology–methods. 5. Pharmacokinetics. 6. Technology, pharmaceutical–methods. 7. Drug Development. 8. Pharmacometrics. QV 744 P5363 2006] RS187.P4553 2006 615′. 1–dc22 2006016629 Printed in the United States of America 10 9 8 7 6 5 4 3 2 1 To my wife, Esther, who supports, comforts, and inspires and is always there for me. E. I. E. To my wife, Debbie, who supports, comforts, and inspires. P. J. W. CONTENTS CONTRIBUTORS xi PREFACE xv ACKNOWLEDGMENTS xix 1. Pharmacometrics: Impacting Drug Development and Pharmacotherapy 1 Paul J. Williams and Ene I. Ette PART I GENERAL PRINCIPLES 2. General Principles of Programming: Computer and Statistical 25 Sastry S. Isukapalli and Amit Roy 3. Validation of Software for Pharmacometric Analysis 53 Gary L. Wolk 4. Linear, Generalized Linear, and Nonlinear Mixed Effects Models 103 Farkad Ezzet and José C. Pinheiro 5. Bayesian Hierarchical Modeling with Markov Chain Monte Carlo Methods 137 Stephen B. Duffull, Lena E. Friberg, and Chantaratsamon Dansirikul 6. Estimating the Dynamics of Drug Regimen Compliance 165 Ene I. Ette and Alaa Ahmad 7. Graphical Displays for Modeling Population Data 183 E. Niclas Jonsson, Mats O. Karlsson, and Peter A. Milligan 8. The Epistemology of Pharmacometrics 223 Paul J. Williams, Yong Ho Kim, and Ene I. Ette 9. Data Imputation 245 Ene I. Ette, Hui-May Chu, and Alaa Ahmad PART II POPULATION PHARMACOKINETIC BASIS OF PHARMACOMETRICS 10. Population Pharmacokinetic Estimation Methods 265 Ene I. Ette, Paul J. Williams, and Alaa Ahmad vii viii CONTENTS 11. Timing and Effi ciency in Population Pharmacokinetic/ Pharmacodynamic Data Analysis Projects 287 Siv Jönsson and E. Niclas Jonsson 12. Designing Population Pharmacokinetic Studies for Effi cient Parameter Estimation 303 Ene I. Ette and Amit Roy 13. Population Models for Drug Absorption and Enterohepatic Recycling 345 Olivier Pétricoul, Valérie Cosson, Eliane Fuseau, and Mathilde Marchand 14. Pharmacometric Knowledge Discovery from Clinical Trial Data Sets 383 Ene I. Ette 15. Resampling Techniques and Their Application to Pharmacometrics 401 Paul J. Williams and Yong Ho Kim 16. Population Modeling Approach in Bioequivalence Assessment 421 Chuanpu Hu and Mark E. Sale PART III PHARMACOKINETICS / PHARMACODYNAMICS RELATIONSHIP: BIOMARKERS AND PHARMACOGENOMICS, PK/PD MODELS FOR CONTINUOUS DATA, AND PK/PD MODELS FOR OUTCOMES DATA 17. Biomarkers in Drug Development and Pharmacometric Modeling 457 Paul J. Williams and Ene I. Ette 18. Analysis of Gene Expression Data 473 Daniel Brazeau and Murali Ramanathan 19. Pharmacogenomics and Pharmacokinetic/Pharmacodynamic Modeling 509 Jin Y. Jin and William J. Jusko 20. Empirical Pharmacokinetic/Pharmacodynamic Models 529 James A. Uchizono and James R. Lane 21. Developing Models of Disease Progression 547 Diane R. Mould 22. Mechanistic Pharmacokinetic/Pharmacodynamic Models I 583 Varun Garg and Ariya Khunvichai 23. Mechanistic Pharmacokinetic/Pharmacodynamic Models II 607 Donald E. Mager and William J. Jusko 24. PK/PD Analysis of Binary (Logistic) Outcome Data 633 Jill Fiedler-Kelly 25. Population Pharmacokinetic/Pharmacodynamic Modeling of Ordered Categorical Longitudinal Data 655 Ene I. Ette, Amit Roy, and Partha Nandy CONTENTS ix 26. Transition Models in Pharmacodynamics 689 Ene I. Ette 27. Mixed Effects Modeling Analysis of Count Data 699 Christopher J. Godfrey 28. Mixture Modeling with NONMEM V 723 Bill Frame PART IV CLINICAL TRIAL DESIGNS 29. Designs for First-Time-in-Human Studies in Nononcology Indications 761 Hui-May Chu, Jiuhong Zha, Amit Roy, and Ene I. Ette 30. Design of Phase 1 Studies in Oncology 781 Brigitte Tranchand, René Bruno, and Gilles Freyer 31. Design and Analysis of Clinical Exposure: Response Trials 803 David Hermann, Raymond Miller, Matthew Hutmacher, Wayne Ewy, and Kenneth Kowalski PART V PHARMACOMETRIC KNOWLEDGE CREATION 32. Pharmacometric/Pharmacodynamic Knowledge Creation: Toward Characterizing an Unexplored Region of the Response Surface 829 Ene I. Ette and Hui-May Chu 33. Clinical Trial Simulation: Theory 851 Peter L. Bonate 34. Modeling and Simulation: Planning and Execution 873 Paul J. Williams and James R. Lane 35. Clinical Trial Simulation: Effi cacy Trials 881 Matthew M. Riggs, Christopher J. Godfrey, and Marc R. Gastanguay PART VI PHARMACOMETRIC SERVICE AND COMMUNICATION 36. Engineering a Pharmacometrics Enterprise 903 Thaddeus H. Grasela and Charles W. Dement 37. Communicating Pharmacometric Analysis Outcome 925 Ene I. Ette and Leonard C. Onyiah PART VII SPECIFIC APPLICATION EXAMPLES 38. Pharmacometrics Applications in Population Exposure–Response Data for New Drug Development and Evaluation 937 He Sun and Emmanuel O. Fadiran x CONTENTS 39. Pharmacometrics in Pharmacotherapy and Drug Development: Pediatric Application 955 Edmund V. Capparelli and Paul J. Williams 40. Pharmacometric Methods for Assessing Drug-Induced QT and QTc Prolongations for Non-antiarrhythmic Drugs 977 He Sun 41. Using Pharmacometrics in the Development of Therapeutic Biological Agents 993 Diane R. Mould 42. Analysis of Quantic Pharmacokinetic Study: Robust Estimation of Tissue-to-Plasma Ratio 1035 Hui-May Chu and Ene I. Ette 43. Physiologically Based Pharmacokinetic Modeling: Inhalation, Ingestion, and Dermal Absorption 1069 Sastry S. Isukapalli, Amit Roy, and Panos G. Georgopoulos 44. Modeling of Metabolite Pharmacokinetics in a Large Pharmacokinetic Data Set: An Application 1107 Valérie Cosson, Karin Jorga, and Eliane Fuseau 45. Characterizing Nonlinear Pharmacokinetics: An Example Scenario for a Therapeutic Protein 1137 Stuart Friedrich 46. Development, Evaluation, and Applications of in Vitro/in Vivo Correlations: A Regulatory Perspective 1157 Patrick J. Marroum 47. The Confl uence of Pharmacometric Knowledge Discovery and Creation in the Characterization of Drug Safety 1175 Hui-May Chu and Ene I. Ette INDEX 1197 CONTRIBUTORS Alaa Ahmad, Clinical Pharmacology, Vertex Pharmaceuticals, 130 Waverly St., Cambridge, MA 02139 [[email protected]] Peter L. Bonate, Genzyme Corporation, Pharmacokinetics, 4545 Horizon Hill Blvd., San Antonio, TX 78229 [[email protected]] Daniel Brazeau, Department of Pharmaceutical Sciences, 517 Cooke Hall, State University of New York at Buffalo, Buffalo, NY 14260 [[email protected]] René Bruno, Pharsight Corporation, 84 Chemin des Grives, 13013 Marseille, France [[email protected]] Edmund V. Capparelli, Pediatric Pharmacology Research Unit, School of Medicine, University of California—San Diego, 4094 4th Avenue, San Diego, CA 92103