DK5184_half-series-title.qxd 2/8/06 10:23 AM Page A Dose Optimization in Drug Development Copyright © 2006 Taylor & Francis Group, LLC DK5184_half-series-title.qxd 2/8/06 10:23 AM Page B DRUGS AND THE PHARMACEUTICAL SCIENCES A Series of Textbooks and Monographs Executive Editor James Swarbrick PharmaceuTech, Inc. Pinehurst, North Carolina Advisory Board Larry L.Augsburger Harry G.Brittain University of Maryland Center for Pharmaceutical Physics Baltimore, Maryland Milford, New Jersey Jennifer B.Dressman Anthony J.Hickey Johann Wolfgang Goethe University University of North Carolina School of Frankfurt, Germany Pharmacy Chapel Hill, North Carolina Jeffrey A.Hughes University of Florida College of Ajaz Hussain Pharmacy U.S.Food and Drug Administration Gainesville, Florida Frederick, Maryland Trevor M.Jones Hans E.Junginger The Association of the Leiden/Amsterdam Center British Pharmaceutical Industry for Drug Research London, United Kingdom Leiden, The Netherlands Vincent H.L.Lee Stephen G.Schulman University of Southern California University of Florida Los Angeles, California Gainesville, Florida Jerome P.Skelly Elizabeth M.Topp Alexandria, Virginia University of Kansas School of Pharmacy Geoffrey T.Tucker Lawrence, Kansas University of Sheffield Royal Hallamshire Hospital Peter York Sheffield, United Kingdom University of Bradford School of Pharmacy Bradford, United Kingdom Copyright © 2006 Taylor & Francis Group, LLC DK5184_half-series-title.qxd 2/8/06 10:23 AM Page C 1. Pharmacokinetics,Milo Gibaldi and Donald Perrier 2. Good Manufacturing Practices for Pharmaceuticals:A Plan for Total Quality Control,Sidney H.Willig, Murray M.Tuckerman, and William S.Hitchings IV 3. Microencapsulation,edited by J.R.Nixon 4. Drug Metabolism:Chemical and Biochemical Aspects,Bernard Testa and PeterJenner 5. New Drugs:Discovery and Development,edited by Alan A.Rubin 6. Sustained and Controlled Release Drug Delivery Systems,edited by Joseph R.Robinson 7. Modern Pharmaceutics,edited by Gilbert S.Banker and Christopher T.Rhodes 8. Prescription Drugs in Short Supply:Case Histories,Michael A.Schwartz 9. Activated Charcoal:Antidotal and Other Medical Uses,David O.Cooney 10. Concepts in Drug Metabolism (in two parts),edited by Peter Jenner and Bernard Testa 11. Pharmaceutical Analysis:Modern Methods (in two parts),edited by James W.Munson 12. Techniques of Solubilization of Drugs,edited by Samuel H.Yalkowsky 13. Orphan Drugs,edited by Fred E.Karch 14. Novel Drug Delivery Systems:Fundamentals, Developmental Concepts, Biomedical Assessments,Yie W.Chien 15. Pharmacokinetics:Second Edition, Revised and Expanded,Milo Gibaldi andDonald Perrier 16. Good Manufacturing Practices for Pharmaceuticals:A Plan for Total Quality Control, Second Edition, Revised and Expanded,Sidney H.Willig, Murray M.Tuckerman, and William S.Hitchings IV 17. Formulation of Veterinary Dosage Forms,edited by Jack Blodinger 18. Dermatological Formulations:Percutaneous Absorption,Brian W.Barry 19. The Clinical Research Process in the Pharmaceutical Industry,edited by Gary M.Matoren 20. Microencapsulation and Related Drug Processes,Patrick B.Deasy 21. Drugs and Nutrients:The Interactive Effects,edited by Daphne A.Roe and T.Colin Campbell 22. Biotechnology of Industrial Antibiotics,Erick J.Vandamme 23. Pharmaceutical Process Validation,edited by Bernard T.Loftus and Robert A.Nash 24. Anticancer and Interferon Agents:Synthesis and Properties,edited by Raphael M.Ottenbrite and George B.Butler 25. Pharmaceutical Statistics:Practical and Clinical Applications, Sanford Bolton Copyright © 2006 Taylor & Francis Group, LLC DK5184_half-series-title.qxd 2/8/06 10:23 AM Page D 26. Drug Dynamics for Analytical, Clinical, and Biological Chemists, Benjamin J.Gudzinowicz, Burrows T.Younkin, Jr., and Michael J.Gudzinowicz 27. Modern Analysis of Antibiotics,edited by Adjoran Aszalos 28. Solubility and Related Properties,Kenneth C.James 29. Controlled Drug Delivery:Fundamentals and Applications, Second Edition, Revised and Expanded,edited by Joseph R.Robinson and Vincent H.Lee 30. New Drug Approval Process:Clinical and Regulatory Management, edited by Richard A.Guarino 31. Transdermal Controlled Systemic Medications,edited by Yie W.Chien 32. Drug Delivery Devices:Fundamentals and Applications,edited by Praveen Tyle 33. Pharmacokinetics:Regulatory • Industrial • Academic Perspectives, edited by Peter G.Welling and Francis L.S.Tse 34. Clinical Drug Trials and Tribulations,edited by Allen E.Cato 35. Transdermal Drug Delivery:Developmental Issues and Research Initiatives,editedby Jonathan Hadgraft and Richard H.Guy 36. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, edited by JamesW.McGinity 37. Pharmaceutical Pelletization Technology,edited by Isaac Ghebre-Sellassie 38. Good Laboratory Practice Regulations,edited by Allen F.Hirsch 39. Nasal Systemic Drug Delivery,Yie W.Chien, Kenneth S.E.Su, and Shyi-Feu Chang 40. Modern Pharmaceutics:Second Edition, Revised and Expanded, edited by GilbertS.Banker and Christopher T.Rhodes 41. Specialized Drug Delivery Systems:Manufacturing and Production Technology,edited by Praveen Tyle 42. Topical Drug Delivery Formulations,edited by David W.Osborne and Anton H.Amann 43. Drug Stability:Principles and Practices,Jens T.Carstensen 44. Pharmaceutical Statistics:Practical and Clinical Applications, Second Edition, Revised and Expanded,Sanford Bolton 45. Biodegradable Polymers as Drug Delivery Systems,edited by Mark Chasin and Robert Langer 46. Preclinical Drug Disposition:A Laboratory Handbook,Francis L.S.Tse and JamesJ.Jaffe 47. HPLC in the Pharmaceutical Industry,edited by Godwin W.Fong and Stanley K.Lam 48. Pharmaceutical Bioequivalence,edited by Peter G.Welling, Francis L.S.Tse, andShrikant V.Dinghe 49. Pharmaceutical Dissolution Testing,Umesh V.Banakar Copyright © 2006 Taylor & Francis Group, LLC DK5184_half-series-title.qxd 2/8/06 10:23 AM Page E 50. Novel Drug Delivery Systems:Second Edition, Revised and Expanded, Yie W.Chien 51. Managing the Clinical Drug Development Process,David M.Cocchetto and Ronald V.Nardi 52. Good Manufacturing Practices for Pharmaceuticals:A Plan for Total Quality Control, Third Edition,edited by Sidney H.Willig and James R.Stoker 53. Prodrugs:Topical and Ocular Drug Delivery, edited by Kenneth B.Sloan 54. Pharmaceutical Inhalation Aerosol Technology, edited by Anthony J.Hickey 55. Radiopharmaceuticals:Chemistry and Pharmacology, edited by Adrian D.Nunn 56. New Drug Approval Process:Second Edition, Revised and Expanded, edited by Richard A.Guarino 57. Pharmaceutical Process Validation:Second Edition, Revised and Expanded, edited by Ira R.Berry and Robert A.Nash 58. Ophthalmic Drug Delivery Systems, edited by Ashim K.Mitra 59. Pharmaceutical Skin Penetration Enhancement, edited by Kenneth A.Walters andJonathan Hadgraft 60. Colonic Drug Absorption and Metabolism, edited by Peter R.Bieck 61. Pharmaceutical Particulate Carriers:Therapeutic Applications, edited by AlainRolland 62. Drug Permeation Enhancement:Theory and Applications, edited by Dean S.Hsieh 63. Glycopeptide Antibiotics, edited by Ramakrishnan Nagarajan 64. Achieving Sterility in Medical and Pharmaceutical Products, Nigel A.Halls 65. Multiparticulate Oral Drug Delivery, edited by Isaac Ghebre-Sellassie 66. Colloidal Drug Delivery Systems, edited by Jörg Kreuter 67. Pharmacokinetics:Regulatory • Industrial • Academic Perspectives, SecondEdition, edited by Peter G.Welling and Francis L.S.Tse 68. Drug Stability:Principles and Practices, Second Edition, Revised and Expanded, Jens T.Carstensen 69. Good Laboratory Practice Regulations:Second Edition, Revised and Expanded, edited by Sandy Weinberg 70. Physical Characterization of Pharmaceutical Solids, edited by Harry G.Brittain 71. Pharmaceutical Powder Compaction Technology, edited by Göran Alderborn and Christer Nyström 72. Modern Pharmaceutics:Third Edition, Revised and Expanded, edited by Gilbert S.Banker and Christopher T.Rhodes 73. Microencapsulation:Methods and Industrial Applications, edited by Simon Benita Copyright © 2006 Taylor & Francis Group, LLC DK5184_half-series-title.qxd 2/8/06 10:23 AM Page F 74. Oral Mucosal Drug Delivery, edited by Michael J.Rathbone 75. Clinical Research in Pharmaceutical Development, edited by Barry Bleidt and Michael Montagne 76. The Drug Development Process:Increasing Efficiency and Cost Effectiveness, edited by Peter G.Welling, Louis Lasagna, and Umesh V.Banakar 77. Microparticulate Systems for the Delivery of Proteins and Vaccines, edited by Smadar Cohen and Howard Bernstein 78. Good Manufacturing Practices for Pharmaceuticals:A Plan for Total Quality Control, Fourth Edition, Revised and Expanded, Sidney H.Willig and James R.Stoker 79. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms: Second Edition, Revised and Expanded, edited by James W.McGinity 80. Pharmaceutical Statistics:Practical and Clinical Applications, Third Edition, Sanford Bolton 81. Handbook of Pharmaceutical Granulation Technology, edited by Dilip M.Parikh 82. Biotechnology of Antibiotics:Second Edition, Revised and Expanded, edited by William R.Strohl 83. Mechanisms of Transdermal Drug Delivery, edited by Russell O.Potts and Richard H.Guy 84. Pharmaceutical Enzymes, edited by Albert Lauwers and Simon Scharpé 85. Development of Biopharmaceutical Parenteral Dosage Forms,edited by John A.Bontempo 86. Pharmaceutical Project Management, edited by Tony Kennedy 87. Drug Products for Clinical Trials:An International Guide to Formulation • Production • Quality Control, edited by Donald C.Monkhouse and Christopher T.Rhodes 88. Development and Formulation of Veterinary Dosage Forms: Second Edition, Revised and Expanded,edited by Gregory E.Hardee and J.Desmond Baggot 89. Receptor-Based Drug Design, edited by Paul Leff 90. Automation and Validation of Information in Pharmaceutical Processing, edited by Joseph F.deSpautz 91. Dermal Absorption and Toxicity Assessment, edited by Michael S.Roberts andKenneth A.Walters 92. Pharmaceutical Experimental Design, Gareth A.Lewis, Didier Mathieu, and RogerPhan-Tan-Luu 93. Preparing for FDA Pre-Approval Inspections, edited by Martin D.Hynes III 94. Pharmaceutical Excipients:Characterization by IR, Raman, and NMR Spectroscopy, David E.Bugay and W.Paul Findlay 95. Polymorphism in Pharmaceutical Solids, edited by Harry G.Brittain Copyright © 2006 Taylor & Francis Group, LLC DK5184_half-series-title.qxd 2/8/06 10:23 AM Page G 96. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products, edited by Louis Rey and Joan C.May 97. Percutaneous Absorption:Drugs–Cosmetics–Mechanisms–Methodology, Third Edition, Revised and Expanded, edited by Robert L.Bronaugh and Howard I.Maibach 98. Bioadhesive Drug Delivery Systems:Fundamentals, Novel Approaches, and Development, edited by Edith Mathiowitz, Donald E.Chickering III, and Claus-Michael Lehr 99. Protein Formulation and Delivery, edited by Eugene J.McNally 100. New Drug Approval Process:Third Edition, The Global Challenge, edited by Richard A.Guarino 101. Peptide and Protein Drug Analysis, edited by Ronald E.Reid 102. Transport Processes in Pharmaceutical Systems, edited by Gordon L.Amidon, PingI.Lee, and Elizabeth M.Topp 103. Excipient Toxicity and Safety,edited by Myra L.Weiner and Lois A.Kotkoskie 104. The Clinical Audit in Pharmaceutical Development,edited by Michael R.Hamrell 105. Pharmaceutical Emulsions and Suspensions, edited by Francoise Nielloud and Gilberte Marti-Mestres 106. Oral Drug Absorption:Prediction and Assessment,edited by Jennifer B.Dressman and Hans Lennernäs 107. Drug Stability:Principles and Practices, Third Edition, Revised and Expanded, editedby Jens T.Carstensen and C.T.Rhodes 108. Containment in the Pharmaceutical Industry, edited by James P.Wood 109. Good Manufacturing Practices for Pharmaceuticals:A Plan for Total Quality Control from Manufacturer to Consumer, Fifth Edition, Revised and Expanded, Sidney H.Willig 110. Advanced Pharmaceutical Solids, Jens T.Carstensen 111. Endotoxins:Pyrogens, LAL Testing, and Depyrogenation, Second Edition, Revisedand Expanded, Kevin L.Williams 112. Pharmaceutical Process Engineering, Anthony J.Hickey and David Ganderton 113. Pharmacogenomics, edited by Werner Kalow, Urs A.Meyer and Rachel F.Tyndale 114. Handbook of Drug Screening, edited by Ramakrishna Seethala and Prabhavathi B.Fernandes 115. Drug Targeting Technology:Physical • Chemical • Biological Methods, edited by Hans Schreier 116. Drug–Drug Interactions, edited by A.David Rodrigues 117. Handbook of Pharmaceutical Analysis, edited by Lena Ohannesian and Anthony J.Streeter 118. Pharmaceutical Process Scale-Up, edited by Michael Levin Copyright © 2006 Taylor & Francis Group, LLC DK5184_half-series-title.qxd 2/8/06 10:23 AM Page H 119. Dermatological and Transdermal Formulations, edited by Kenneth A.Walters 120. Clinical Drug Trials and Tribulations:Second Edition, Revised and Expanded,edited by Allen Cato, Lynda Sutton, and Allen Cato III 121. Modern Pharmaceutics:Fourth Edition, Revised and Expanded,edited by GilbertS.Banker and Christopher T.Rhodes 122. Surfactants and Polymers in Drug Delivery, Martin Malmsten 123. Transdermal Drug Delivery:Second Edition, Revised and Expanded, edited by Richard H.Guy and Jonathan Hadgraft 124. Good Laboratory Practice Regulations:Second Edition, Revised and Expanded, edited by Sandy Weinberg 125. Parenteral Quality Control:Sterility, Pyrogen, Particulate, and Package Integrity Testing:Third Edition, Revised and Expanded, Michael J.Akers, Daniel S.Larrimore,and Dana Morton Guazzo 126. Modified-Release Drug Delivery Technology,edited by Michael J.Rathbone, Jonathan Hadgraft, and Michael S.Roberts 127. Simulation for Designing Clinical Trials:A Pharmacokinetic- Pharmacodynamic Modeling Perspective,edited by Hui C.Kimko and Stephen B.Duffull 128. Affinity Capillary Electrophoresis in Pharmaceutics and Biopharmaceutics, editedby Reinhard H.H.Neubert and Hans-Hermann Rüttinger 129. Pharmaceutical Process Validation:An International Third Edition, Revised andExpanded, edited by Robert A.Nash and Alfred H.Wachter 130. Ophthalmic Drug Delivery Systems:Second Edition, Revised and Expanded, edited by Ashim K.Mitra 131. Pharmaceutical Gene Delivery Systems, edited by Alain Rolland and Sean M.Sullivan 132. Biomarkers in Clinical Drug Development, edited by John C.Bloom and Robert A.Dean 133. Pharmaceutical Extrusion Technology, edited by Isaac Ghebre-Sellassie and Charles Martin 134. Pharmaceutical Inhalation Aerosol Technology:Second Edition, Revised and Expanded, edited by Anthony J.Hickey 135. Pharmaceutical Statistics:Practical and Clinical Applications, Fourth Edition, Sanford Bolton and Charles Bon 136. Compliance Handbook for Pharmaceuticals, Medical Devices, and Biologics, edited by Carmen Medina 137. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products: SecondEdition, Revised and Expanded, edited by Louis Rey and Joan C.May 138. Supercritical Fluid Technology for Drug Product Development, edited by Peter York, Uday B.Kompella, and Boris Y.Shekunov 139. New Drug Approval Process:Fourth Edition, Accelerating Global Registrations,edited by Richard A.Guarino Copyright © 2006 Taylor & Francis Group, LLC DK5184_half-series-title.qxd 2/8/06 10:23 AM Page I 140. Microbial Contamination Control in Parenteral Manufacturing, edited by Kevin L.Williams 141. New Drug Development:Regulatory Paradigms for Clinical Pharmacology andBiopharmaceutics, edited by Chandrahas G.Sahajwalla 142. Microbial Contamination Control in the Pharmaceutical Industry, edited by LuisJimenez 143. Generic Drug Product Development:Solid Oral Dosage Forms, edited by Leon Shargel and Izzy Kanfer 144. Introduction to the Pharmaceutical Regulatory Process, edited by Ira R.Berry 145. Drug Delivery to the Oral Cavity:Molecules to Market, edited by Tapash K.Ghosh and William R.Pfister 146. Good Design Practices for GMP Pharmaceutical Facilities, edited by Andrew Signore and Terry Jacobs 147. Drug Products for Clinical Trials, Second Edition, edited by Donald Monkhouse, Charles Carney, and Jim Clark 148. Polymeric Drug Delivery Systems, edited by Glen S.Kwon 149. Injectable Dispersed Systems:Formulation, Processing, and Performance, edited by Diane J.Burgess 150. Laboratory Auditing for Quality and Regulatory Compliance, Donald Singer, Raluca-Ioana Stefan, and Jacobus van Staden 151. Active Pharmaceutical Ingredients:Development, Manufacturing, and Regulation, edited by Stanley Nusim 152. Preclinical Drug Development, edited by Mark C.Rogge and David R.Taft 153. Pharmaceutical Stress Testing:Predicting Drug Degradation, edited by Steven W.Baertschi 154. Handbook of Pharmaceutical Granulation Technology:Second Edition, edited by Dilip M.Parikh 155. Percutaneous Absorption:Drugs–Cosmetics–Mechanisms–Methodology, Fourth Edition, edited by Robert L.Bronaugh and Howard I.Maibach 156. Pharmacogenomics:Second Edition, edited by Werner Kalow, Urs A.Meyer and Rachel F.Tyndale 157. Pharmaceutical Process Scale-Up, Second Edition, edited by Michael Levin 158. Microencapsulation:Methods and Industrial Applications, Second Edition, edited by Simon Benita 159. Nanoparticle Technology for Drug Delivery, edited by Ram B.Gupta and Uday B.Kompella 160. Spectroscopy of Pharmaceutical Solids, edited by Harry G.Brittain 161. Dose Optimization in Drug Development, edited by Rajesh Krishna 162. Herbal Supplements-Drug Interactions:Scientific and Regulatory Perspectives, edited by Y.W.Francis Lam, Shiew-Mei Huang, and Stephen D.Hall Copyright © 2006 Taylor & Francis Group, LLC DK5184_half-series-title.qxd 3/27/06 1:46 PM Page i Dose Optimization in Drug Development edited by Rajesh Krishna Merck & Co., Inc. Rahway, New Jersey, U.S.A. New York London Copyright © 2006 Taylor & Francis Group, LLC