HONGHUI ZHOU, PhD, is Senior Scientific Director and Janssen Fellow, Janssen Research & Development, LLC, Johnson & Johnson, where he heads the Pharmacokinetics & Pharma-codynamics Department within Biologics Clinical Pharmacology. Board-certified by the American Board of Clinical Pharmacology and an American College of Clinical Pharmacology Fellow, Dr. Zhou has authored more than 150 peer-reviewed scientific papers, book chapters, and conference abstracts in pharmacokinetics, pharmacodynamics, and drug-drug interactions.BERND MEIBOHM, PhD, is Professor of Pharmaceutical Sciences and Associate Dean for Research and Graduate Programs at the College of Pharmacy, The University of Tennessee Health Science Center. Dr. Meibohm is a Fellow of the American Association of Pharmaceutical Scientists and the American College of Clinical Pharmacology.

• PREFACE ixABOUT THE EDITORS xiCONTRIBUTORS xiii1. DRUG INTERACTIONS FOR THERAPEUTIC PROTEINS: A JOURNEY JUST BEGINNING 1Honghui Zhou and Bernd Meibohm2. PHARMACOKINETIC AND PHARMACODYNAMIC-BASED DRUG INTERACTIONS FOR THERAPEUTIC PROTEINS 5Dan Lu, Sandhya Girish, Frank-Peter Theil, and Amita Joshi3. DRUG INTERACTION ASSESSMENT STRATEGIES: SMALL MOLECULES VERSUS THERAPEUTIC PROTEINS 39Shannon Dallas, Carlo Sensenhauser, Souvik Chattopadhyay, and Jose Silva4. MODEL-INDEPENDENT AND MODEL-BASED METHODS TO ASSESS DRUG–DRUG INTERACTIONS FOR THERAPEUTIC PROTEINS 63Di Wu and Jeffrey S. Barrett5. UTILITY OF IN VITRO METHODS IN DRUG–DRUG INTERACTION ASSESSMENT AND PREDICTION FOR THERAPEUTIC BIOLOGICS 73Theresa Nguyen, Narendra Kishnani, and Raymond Evers6. USE OF ANIMAL MODELS FOR PROJECTION OF CLINICAL DRUG–DRUG INTERACTIONS FOR THERAPEUTIC PROTEINS 103Eugenia Kraynov and Martin E. Dowty7. THE COCKTAIL APPROACH AND ITS UTILITY IN DRUG–DRUG INTERACTION ASSESSMENTS FOR THERAPEUTIC PROTEINS 111Alexander Jetter and Uwe Fuhr8. LOGISTIC CONSIDERATIONS IN STUDY DESIGN FOR BIOLOGIC DRUG–DRUG INTERACTION ASSESSMENTS 119Min Zhu and Yu-Nien (Tom) Sun9. STATISTICAL CONSIDERATIONS IN ASSESSING DRUG–DRUG INTERACTIONS FOR THERAPEUTIC BIOLOGICS 139Chuanpu Hu and Honghui Zhou10. SCIENTIFIC PERSPECTIVES ON THERAPEUTIC PROTEIN DRUG–DRUG INTERACTION ASSESSMENTS 155Hong Zhao, Lei Zhang, Kellie Reynolds, and Shiew-Mei Huang11. DISEASE–DRUG–DRUG INTERACTION ASSESSMENTS FOR TOCILIZUMAB—A MONOCLONAL ANTIBODY AGAINST INTERLEUKIN-6 RECEPTOR TO TREAT PATIENTS WITH RHEUMATOID ARTHRITIS 191Xiaoping Zhang and Barbara J. Brennan12. DRUG–DRUG INTERACTIONS FOR ETANERCEPT—A FUSION PROTEIN 207Joan Korth-Bradley13. DRUG INTERACTIONS OF CYTOKINES AND ANTICYTOKINE THERAPEUTIC PROTEINS 215J. Greg Slatter, Larry C. Wienkers, and Leslie J. Dickmann14. DRUG INTERACTIONS FOR GROWTH FACTORS AND HORMONES 239Yow-Ming C. Wang and Tarundeep Kakkar15. DRUG–DRUG INTERACTIONS FOR NUCLEIC ACID-BASED DERIVATIVES 257Jian Wang and Hong ZhaoAPPENDIX: MONOGRAPHS FOR DRUG-DRUG INTERACTIONS OF THERAPEUTICS BIOLOGICS 275Jocelyn Leu, Simone Kasek, Christine Li, Wararat Limothai, Dora Babu Madhura, Chetan Rathi, Sumit Rawal, Josiah Ryman, Margaret Thomson, Ashit Trivedi, Honghui Zhou, and Bernd MeibohmINDEX 351

HONGHUI ZHOU, PhD, is Senior Scientific Director and Janssen Fellow, Janssen Research & Development, LLC, Johnson & Johnson, where he heads the Pharmacokinetics & Pharma-codynamics Department within Biologics Clinical Pharmacology. Board-certified by the American Board of Clinical Pharmacology and an American College of Clinical Pharmacology Fellow, Dr. Zhou has authored more than 150 peer-reviewed scientific papers, book chapters, and conference abstracts in pharmacokinetics, pharmacodynamics, and drug-drug interactions.BERND MEIBOHM, PhD, is Professor of Pharmaceutical Sciences and Associate Dean for Research and Graduate Programs at the College of Pharmacy, The University of Tennessee Health Science Center. Dr. Meibohm is a Fellow of the American Association of Pharmaceutical Scientists and the American College of Clinical Pharmacology.

• PREFACE ixABOUT THE EDITORS xiCONTRIBUTORS xiii1. DRUG INTERACTIONS FOR THERAPEUTIC PROTEINS: A JOURNEY JUST BEGINNING 1Honghui Zhou and Bernd Meibohm2. PHARMACOKINETIC AND PHARMACODYNAMIC-BASED DRUG INTERACTIONS FOR THERAPEUTIC PROTEINS 5Dan Lu, Sandhya Girish, Frank-Peter Theil, and Amita Joshi3. DRUG INTERACTION ASSESSMENT STRATEGIES: SMALL MOLECULES VERSUS THERAPEUTIC PROTEINS 39Shannon Dallas, Carlo Sensenhauser, Souvik Chattopadhyay, and Jose Silva4. MODEL-INDEPENDENT AND MODEL-BASED METHODS TO ASSESS DRUG–DRUG INTERACTIONS FOR THERAPEUTIC PROTEINS 63Di Wu and Jeffrey S. Barrett5. UTILITY OF IN VITRO METHODS IN DRUG–DRUG INTERACTION ASSESSMENT AND PREDICTION FOR THERAPEUTIC BIOLOGICS 73Theresa Nguyen, Narendra Kishnani, and Raymond Evers6. USE OF ANIMAL MODELS FOR PROJECTION OF CLINICAL DRUG–DRUG INTERACTIONS FOR THERAPEUTIC PROTEINS 103Eugenia Kraynov and Martin E. Dowty7. THE COCKTAIL APPROACH AND ITS UTILITY IN DRUG–DRUG INTERACTION ASSESSMENTS FOR THERAPEUTIC PROTEINS 111Alexander Jetter and Uwe Fuhr8. LOGISTIC CONSIDERATIONS IN STUDY DESIGN FOR BIOLOGIC DRUG–DRUG INTERACTION ASSESSMENTS 119Min Zhu and Yu-Nien (Tom) Sun9. STATISTICAL CONSIDERATIONS IN ASSESSING DRUG–DRUG INTERACTIONS FOR THERAPEUTIC BIOLOGICS 139Chuanpu Hu and Honghui Zhou10. SCIENTIFIC PERSPECTIVES ON THERAPEUTIC PROTEIN DRUG–DRUG INTERACTION ASSESSMENTS 155Hong Zhao, Lei Zhang, Kellie Reynolds, and Shiew-Mei Huang11. DISEASE–DRUG–DRUG INTERACTION ASSESSMENTS FOR TOCILIZUMAB—A MONOCLONAL ANTIBODY AGAINST INTERLEUKIN-6 RECEPTOR TO TREAT PATIENTS WITH RHEUMATOID ARTHRITIS 191Xiaoping Zhang and Barbara J. Brennan12. DRUG–DRUG INTERACTIONS FOR ETANERCEPT—A FUSION PROTEIN 207Joan Korth-Bradley13. DRUG INTERACTIONS OF CYTOKINES AND ANTICYTOKINE THERAPEUTIC PROTEINS 215J. Greg Slatter, Larry C. Wienkers, and Leslie J. Dickmann14. DRUG INTERACTIONS FOR GROWTH FACTORS AND HORMONES 239Yow-Ming C. Wang and Tarundeep Kakkar15. DRUG–DRUG INTERACTIONS FOR NUCLEIC ACID-BASED DERIVATIVES 257Jian Wang and Hong ZhaoAPPENDIX: MONOGRAPHS FOR DRUG-DRUG INTERACTIONS OF THERAPEUTICS BIOLOGICS 275Jocelyn Leu, Simone Kasek, Christine Li, Wararat Limothai, Dora Babu Madhura, Chetan Rathi, Sumit Rawal, Josiah Ryman, Margaret Thomson, Ashit Trivedi, Honghui Zhou, and Bernd MeibohmINDEX 351

HONGHUI ZHOU, PhD, is Senior Scientific Director and Janssen Fellow, Janssen Research & Development, LLC, Johnson & Johnson, where he heads the Pharmacokinetics & Pharma-codynamics Department within Biologics Clinical Pharmacology. Board-certified by the American Board of Clinical Pharmacology and an American College of Clinical Pharmacology Fellow, Dr. Zhou has authored more than 150 peer-reviewed scientific papers, book chapters, and conference abstracts in pharmacokinetics, pharmacodynamics, and drug-drug interactions.BERND MEIBOHM, PhD, is Professor of Pharmaceutical Sciences and Associate Dean for Research and Graduate Programs at the College of Pharmacy, The University of Tennessee Health Science Center. Dr. Meibohm is a Fellow of the American Association of Pharmaceutical Scientists and the American College of Clinical Pharmacology.

• PREFACE ixABOUT THE EDITORS xiCONTRIBUTORS xiii1. DRUG INTERACTIONS FOR THERAPEUTIC PROTEINS: A JOURNEY JUST BEGINNING 1Honghui Zhou and Bernd Meibohm2. PHARMACOKINETIC AND PHARMACODYNAMIC-BASED DRUG INTERACTIONS FOR THERAPEUTIC PROTEINS 5Dan Lu, Sandhya Girish, Frank-Peter Theil, and Amita Joshi3. DRUG INTERACTION ASSESSMENT STRATEGIES: SMALL MOLECULES VERSUS THERAPEUTIC PROTEINS 39Shannon Dallas, Carlo Sensenhauser, Souvik Chattopadhyay, and Jose Silva4. MODEL-INDEPENDENT AND MODEL-BASED METHODS TO ASSESS DRUG–DRUG INTERACTIONS FOR THERAPEUTIC PROTEINS 63Di Wu and Jeffrey S. Barrett5. UTILITY OF IN VITRO METHODS IN DRUG–DRUG INTERACTION ASSESSMENT AND PREDICTION FOR THERAPEUTIC BIOLOGICS 73Theresa Nguyen, Narendra Kishnani, and Raymond Evers6. USE OF ANIMAL MODELS FOR PROJECTION OF CLINICAL DRUG–DRUG INTERACTIONS FOR THERAPEUTIC PROTEINS 103Eugenia Kraynov and Martin E. Dowty7. THE COCKTAIL APPROACH AND ITS UTILITY IN DRUG–DRUG INTERACTION ASSESSMENTS FOR THERAPEUTIC PROTEINS 111Alexander Jetter and Uwe Fuhr8. LOGISTIC CONSIDERATIONS IN STUDY DESIGN FOR BIOLOGIC DRUG–DRUG INTERACTION ASSESSMENTS 119Min Zhu and Yu-Nien (Tom) Sun9. STATISTICAL CONSIDERATIONS IN ASSESSING DRUG–DRUG INTERACTIONS FOR THERAPEUTIC BIOLOGICS 139Chuanpu Hu and Honghui Zhou10. SCIENTIFIC PERSPECTIVES ON THERAPEUTIC PROTEIN DRUG–DRUG INTERACTION ASSESSMENTS 155Hong Zhao, Lei Zhang, Kellie Reynolds, and Shiew-Mei Huang11. DISEASE–DRUG–DRUG INTERACTION ASSESSMENTS FOR TOCILIZUMAB—A MONOCLONAL ANTIBODY AGAINST INTERLEUKIN-6 RECEPTOR TO TREAT PATIENTS WITH RHEUMATOID ARTHRITIS 191Xiaoping Zhang and Barbara J. Brennan12. DRUG–DRUG INTERACTIONS FOR ETANERCEPT—A FUSION PROTEIN 207Joan Korth-Bradley13. DRUG INTERACTIONS OF CYTOKINES AND ANTICYTOKINE THERAPEUTIC PROTEINS 215J. Greg Slatter, Larry C. Wienkers, and Leslie J. Dickmann14. DRUG INTERACTIONS FOR GROWTH FACTORS AND HORMONES 239Yow-Ming C. Wang and Tarundeep Kakkar15. DRUG–DRUG INTERACTIONS FOR NUCLEIC ACID-BASED DERIVATIVES 257Jian Wang and Hong ZhaoAPPENDIX: MONOGRAPHS FOR DRUG-DRUG INTERACTIONS OF THERAPEUTICS BIOLOGICS 275Jocelyn Leu, Simone Kasek, Christine Li, Wararat Limothai, Dora Babu Madhura, Chetan Rathi, Sumit Rawal, Josiah Ryman, Margaret Thomson, Ashit Trivedi, Honghui Zhou, and Bernd MeibohmINDEX 351