DRUG-DRUG INTERACTIONS FOR THERAPEUTIC BIOLOGICS -- CONTENTS -- PREFACE -- ABOUT THE EDITORS -- CONTRIBUTORS -- 1. DRUG INTERACTIONS FOR THERAPEUTIC PROTEINS: A JOURNEY JUST BEGINNING -- 1.1 INTRODUCTION -- 1.2 SCIENTIFIC/REGULATORY LANDSCAPE OF THERAPEUTIC PROTEIN-DRUG INTERACTIONS -- REFER ENCE S -- 2. PHARMACOKINETIC AND PHARMACODYNAMIC-BASED DRUG INTERACTIONS FOR THERAPEUTIC PROTEINS -- 2.1 INTRODUCTION -- 2.2 DISTRIBUTION, CATABOLISM/METABOLISM, AND EXCRETION MECHANISMS OF THERAPEUTIC PROTEINS -- 2.2.1 Distribution of Therapeutic Proteins -- 2.2.2 Catabolism of Therapeutic Proteins -- 2.2.3 Excretion of Therapeutic Proteins -- 2.2.4 Pharmacokinetic Properties of Antibody-Drug Conjugates -- 2.3 MAJOR MECHANISMS OF THERAPEUTIC PROTEIN-DRUG INTERACTIONS -- 2.3.1 Impact of Pharmacokinetic-Based Therapeutic Protein-Drug Interactions on the Exposures of Therapeutic Proteins and Small Molecule Drugs -- 2.3.2 Impact of Pharmacodynamic-Based Therapeutic Protein-Drug Interactions on the Exposure of Therapeutic Proteins -- 2.3.3 Impact of Pharmacodynamic-Based Therapeutic Protein-Drug Interactions on the Exposure of Small Molecule Drugs Owing to Therapeutic Protein-Cytokine-Cytochrome P450 Modulation Effects -- 2.3.4 Pharmacodynamic-Based Therapeutic Protein-Drug Interactions That Lead to Toxicity without Affecting Exposures -- 2.4 STRATEGIES TO ASSESS THE RISK OF THERAPEUTIC PROTEIN-DRUG INTERACTIONS IN CLINICAL DEVELOPMENT OF THERAPEUTIC PROTEINS -- 2.4.1 Challenges of Assessing Therapeutic Protein-Drug Interactions in Clinical Development -- 2.4.2 Question-Based Strategy of Therapeutic Protein-Drug Interaction Assessment During Clinical Development -- 2.5 SUMMARY -- ACKNOWL EDGMEN TS -- REFERENCES -- 3. DRUG INTERACTION ASSESSMENT STRATEGIES: SMALL MOLECULES VERSUS THERAPEUTIC PROTEINS -- 3.1 INTRODUCTION -- 3.2 DRUG-METABOLIZING ENZYMES.

3.2.1 Cytochrome P450 Enzymes -- 3.2.2 Inhibition -- 3.2.3 Reaction Phenotyping -- 3.2.4 Induction and Suppression -- 3.3 TRANSPORTERS -- 3.3.1 Substrate and Inhibitor Studies -- 3.3.2 Induction and Suppression -- 3.4 CONCLUSION -- REFERENCES -- 4. MODEL-INDEPENDENT AND MODEL-BASED METHODS TO ASSESS DRUG-DRUG INTERACTIONS FOR THERAPEUTIC PROTEINS -- 4.1 INTRODUCTION -- 4.2 TP-DIs -- 4.2.1 Therapeutic Target and Window -- 4.3 IN VITRO AND IN VIVO APPROACHES FOR EVALUATING TP-DI -- 4.3.1 In Vitro Screening -- 4.3.2 Clinical DDI Investigations -- 4.3.3 Model-Based Method: Population PK/PD-based DDI Study -- 4.4 BIOANALYTICAL CONSIDERATIONS -- 4.5 CONCLUSION -- REFERENCES -- 5. UTILITY OF IN VITRO METHODS IN DRUG-DRUG INTERACTION ASSESSMENT AND PREDICTION FOR THERAPEUTIC BIOLOGICS -- 5.1 INTRODUCTION -- 5.2 MECHANISMS INVOLVED IN SUPPRESSION OF DRUG-METABOLIZING ENZYMES -- 5.3 IN VITRO ASSAYS -- 5.4 EFFECTS OF CYTOKINES ON METABOLIZING ENZYMES AND TRANSPORTERS -- 5.4.1 IL-1 Investigations -- 5.4.2 IL-2 Investigations -- 5.4.3 IL-4 Investigations -- 5.4.4 IL-6 Investigations -- 5.4.5 Oncostatin -- 5.4.6 TNF-α Investigations -- 5.4.7 IFN Investigations -- 5.5 SUMMARY AND CONCLUSION -- REFERENCES -- 6. USE OF ANIMAL MODELS FOR PROJECTION OF CLINICAL DRUG-DRUG INTERACTIONS FOR THERAPEUTIC PROTEINS -- 6.1 INTRODUCTION -- 6.2 SELECTION OF THE ANIMAL MODEL -- 6.3 STUDY DESIGN -- 6.4 DISEASE MODELS -- 6.5 EMERGING CHALLENGES -- 6.6 CONCLUSIONS -- REFERENCES -- 7. THE COCKTAIL APPROACH AND ITS UTILITY IN DRUG-DRUG INTERACTION ASSESSMENTS FOR THERAPEUTIC PROTEINS -- 7.1 ASSESSMENT OF ENZYME ACTIVITIES USING THE COCKTAIL APPROACH -- 7.2 GUIDELINES APPLICABLE FOR COCKTAIL DRUG-DRUG INTERACTION STUDIES -- 7.3 COCKTAIL INTERACTION STUDIES WITH THERAPEUTIC PROTEINS: SPECIAL FEATURES -- 7.4 PUBLISHED COCKTAIL INTERACTION STUDIES WITH THERAPEUTIC PROTEINS.

7.5 CONCLUSIONS -- REFERENCES -- 8. LOGISTIC CONSIDERATIONS IN STUDY DESIGN FOR BIOLOGIC DRUG-DRUG INTERACTION ASSESSMENTS -- 8.1 INTRODUCTION -- 8.2 CHALLENGES IN THE CONDUCT OF A TP-DRUG INTERACTION STUDY -- 8.3 TP-DRUG INTERACTION STUDY DESIGN -- 8.3.1 Screening Study for TP-Drug Interactions -- 8.3.2 Estimation Study for TP-Drug Interaction -- 8.3.3 Dedicated Study for TP-Drug Interaction -- 8.4 TIMING OF TP-DRUG INTERACTION STUDY -- 8.5 STRATEGIC PLANNING OF TP-DRUG INTERACTION STUDIES -- 8.5.1 Oncology -- 8.5.2 Immunology and Inflammation -- 8.6 CONSIDERATIONS IN STUDY DESIGN -- 8.6.1 Study Population -- 8.6.2 Selection of Interacting Drugs -- 8.6.3 Type of Study Design -- 8.6.4 Regimen Selection -- 8.6.5 Sampling Scheme -- 8.6.6 Endpoints for TP-Drug Interaction Evaluation -- 8.6.7 Sample Size -- 8.6.8 Criteria for TP-Drug Interaction Evaluation -- 8.7 DATA ANALYSIS -- 8.7.1 Noncompartment Analysis -- 8.7.2 Population Pharmacokinetic Modeling -- 8.8 PROSPECTIVELY DESIGN OF TP-DRUG INTERACTION STUDY -- 8.9 SUMMARY -- REFERENCES -- 9. STATISTICAL CONSIDERATIONS IN ASSESSING DRUG-DRUG INTERACTIONS FOR THERAPEUTIC BIOLOGICS -- 9.1 INTRODUCTION -- 9.2 METHODOLOGY FOR DRUG-DRUG INTERACTION ASSESSMENTS -- 9.2.1 Conventional DDI Assessment -- 9.2.2 Population Pharmacokinetics Based DDI Assessments -- 9.2.3 Comparison between Traditional and Population PK Based DDI Assessments -- 9.3 POPULATION PHARMACOKINETICS FOR DRUG-DRUG INTERACTION ASSESSMENTS: USTEKINUMAB -- 9.3.2 Confirmatory Population Pharmacokinetic Analysis Plan -- 9.3.3 Covariate and Drug-Drug Interaction Effect Assessment -- 9.4 SUMMARY -- REFERENCES -- 10. SCIENTIFIC PERSPECTIVES ON THERAPEUTIC PROTEIN DRUG-DRUG INTERACTION ASSESSMENTS -- 10.1 INTRODUCTION -- 10.2 THERAPEUTIC PROTEIN-DRUG INTERACTION STUDIES -- 10.3 TYPES OF STUDY DESIGNS -- 10.4 LABELING IMPLICATIONS -- 10.5 CON CLUSIO N.

REFERENCES -- 11. DISEASE-DRUG-DRUG INTERACTION ASSESSMENTS FOR TOCILIZUMAB-A MONOCLONAL ANTIBODY AGAINST INTERLEUKIN-6 RECEPTOR TO TREAT PATIENTS WITH RHEUMATOID ARTHRITIS -- 11.1 INTRODUCTION -- 11.2 PRECLINICAL EVALUATION -- 11.3 CLINICAL DDDI EVALUATIONS -- 11.3.1 Omeprazole DDDI Evaluation -- 11.3.2 Dextromethorphan DDDI Evaluation -- 11.3.3 Simvastatin DDDI Evaluation -- 11.3.4 Methotrexate DDDI Evaluation -- 11.3.5 Additional Drug-Drug Interaction Evaluations -- 11.4 LABELING -- 11.5 DISCUSSION -- REFERENCES -- 12. DRUG-DRUG INTERACTIONS FOR ETANERCEPT-A FUSION PROTEIN -- 12.1 ETANERCEPT BACKGROUND -- 12.2 MECHANISMS OF DRUG INTERACTIONS -- 12.3 PHARMACODYNAMIC DRUG INTERACTIONS -- 12.4 RESULTS OF DRUG INTERACTION STUDIES WITH ETANERCEPT -- 12.5 CONCLUSIONS -- ACKNOWLEDGMENTS AND CONFLICTS OF INTEREST -- REFERENCES -- 13. DRUG INTERACTIONS OF CYTOKINES AND ANTICYTOKINE THERAPEUTIC PROTEINS -- 13.1 INTRODUCTION -- 13.2 CLINICAL RELEVANCE OF CYTOKINE-MEDIATED SUPPRESSION AND DESUPPRESSION OF ADME ENZYMES -- 13.2.1 Treatment with Interferons and Related Proinflammatory Agents -- 13.2.2 Treatment of Inflammatory Conditions through the Mitigation of Cytokine-Mediated Signaling -- 13.2.3 The Tocilizumab-Simvastatin Interaction -- 13.2.4 Can C-reactive Protein (CRP) and/or IL-6 Be Used to Predict the Clinical Magnitude of CYP Suppression and Desuppression? -- 13.3 MECHANISM -- 13.3.1 Cytokine-Mediated Suppression of CYPs -- 13.3.2 A Related Mechanism: Drug Binding to α1-Acid Glycoprotein -- 13.4 CAN PRECLINICAL MODELS BE USED TO PREDICT CLINICAL SUPPRESSION OR DESUPPRESSION? -- 13.4.1 Cytokine Effects in Hepatocyte Culture: Studies on IL-6 -- 13.4.2 Is Interleukin-6 Always Involved When Hepatic CYP Suppression Occurs? -- 13.4.3 Recapitulating Hepatic Inflammation in vitro with Cytokine Combinations.

13.4.4 CYP Suppression and Desuppression in Murine Models of Inflammatory Disease In Vivo -- 13.4.5 In Vivo/In Vitro Similarities and Differences between the CAIA Model and Cultured Mouse Hepatocytes Treated with a Cytokine Cocktail -- 13.4.6 Are In Vitro Data Adequate to Preclude the Need for a Clinical DDI Study? -- 13.5 CURRENT REGULATORY PERSPECTIVE -- 13.6 CLINICAL OPTIONS -- 13.7 CONCLUSIONS -- ACKNOWLEDGMENTS -- DECLARATION OF INTEREST -- REFERENCES -- 14. DRUG INTERACTIONS FOR GROWTH FACTORS AND HORMONES -- 14.1 INTRODUCTION -- 14.2 GROWTH FACTORS -- 14.2.1 Erythropoiesis-Stimulating Agents -- 14.2.2 Granulocyte Colony Stimulating Factor -- 14.2.3 Kerat inocyte Growt h Fact or -- 14.2.4 Thrombopoiesis-Stimulating Agents -- 14.3 HORMONES -- 14.3.1 Human Growth Hormone -- 14.3.2 Pegvisomant -- 14.3.3 Glucagon -- 14.4 CONCLUSIONS -- REFERENCES -- 15. DRUG-DRUG INTERACTIONS FOR NUCLEIC ACID-BASED DERIVATIVES -- 15.1 INTRODUCTION -- 15.2 CLINICAL PHARMACOKINETICS -- 15.3 DRUG-DRUG INTERACTIONS -- 15.3.1 In Vitro Studies -- 15.3.2 DDI Studies in Animals -- 15.3.3 DDI Studies in Humans -- 15.4 OTHER CONSIDERATIONS -- 15.4.1 Indirect Effects on CYP Enzymes -- 15.4.2 Immunogenicity and Its Effects on PK -- 15.4.3 Considerations of DDI Studies -- 15.4.4 Regulatory Perspective -- 15.5 SUMMARY -- REFERENCES -- APPENDIX: MONOGRAPHS FOR DRUG-DRUG INTERACTIONS OF THERAPEUTICS BIOLOGICS -- INDEX.