Drug-Drug Interactions for Therapeutic Biologics

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