ADME-Enabling Technologies in Drug Design and Development -- CONTENTS -- FOREWORD -- PREFACE -- CONTRIBUTORS -- PART A: ADME: OVERVIEW AND CURRENT TOPICS -- 1: REGULATORY DRUG DISPOSITION AND NDA PACKAGE INCLUDING MIST -- 1.1 INTRODUCTION -- 1.2 NONCLINICAL OVERVIEW -- 1.3 PK -- 1.4 ABSORPTION -- 1.5 DISTRIBUTION -- 1.5.1 Plasma Protein Binding -- 1.5.2 Tissue Distribution -- 1.5.3 Lacteal and Placental Distribution Studies -- 1.6 METABOLISM -- 1.6.1 In vitro Metabolism Studies -- 1.6.2 Drug-Drug Interaction Studies -- 1.6.3 In vivo Metabolism (ADME) Studies -- 1.7 EXCRETION -- 1.8 IMPACT OF METABOLISM INFORMATION ON LABELING -- 1.9 CONCLUSIONS -- REFERENCES -- 2: OPTIMAL ADME PROPERTIES FOR CLINICAL CANDIDATE AND INVESTIGATIONAL NEW DRUG (IND) PACKAGE -- 2.1 INTRODUCTION -- 2.2 NCE AND INVESTIGATIONAL NEW DRUG (IND) PACKAGE -- 2.3 ADME OPTIMIZATION -- 2.3.1 Absorption -- 2.3.2 Metabolism -- 2.3.3 PK -- 2.4 ADME OPTIMIZATION FOR CNS DRUGS -- 2.5 SUMMARY -- REFERENCES -- 3: DRUG TRANSPORTERS IN DRUG INTERACTIONS AND DISPOSITION -- 3.1 INTRODUCTION -- 3.2 ABC TRANSPORTERS -- 3.2.1 Pgp (MDR1, ABCB1) -- 3.2.2 BCRP (ABCG2) -- 3.2.3 MRP2 (ABCC2) -- 3.3 SLC TRANSPORTERS -- 3.3.1 OCT1 (SLC22A1) and OCT2 (SLC22A2) -- 3.3.2 MATE1 (SLC47A1) and MATE2K (SLC47A2) -- 3.3.3 OAT1 (SLC22A6) and OAT3 (SLC22A8) -- 3.3.4 OATP1B1 (SLCO1B1, SLC21A6), OATP1B3 (SLCO1B3, SLC21A8), and OATP2B1 (SLCO2B1, SLC21A9) -- 3.4 IN VITRO ASSAYS IN DRUG DEVELOPMENT -- 3.4.1 Considerations for Assessing Candidate Drugs as Inhibitors -- 3.4.2 Considerations for Assessing Candidate Drugs as Substrates -- 3.4.3 Assay Systems -- 3.5 CONCLUSIONS AND PERSPECTIVES -- REFERENCES -- 4: PHARMACOLOGICAL AND TOXICOLOGICAL ACTIVITY OF DRUG METABOLITES -- 4.1 INTRODUCTION -- 4.2 ASSESSMENT OF POTENTIAL FOR ACTIVE METABOLITES -- 4.2.1 Detection of Active Metabolites during Drug Discovery.

4.2.2 Methods for Assessing and Evaluating the Biological Activity of Metabolite Mixtures -- 4.2.3 Methods for Generation of Metabolites -- 4.3 ASSESSMENT OF THE POTENTIAL TOXICOLOGY OF METABOLITES -- 4.3.1 Methods to Study the Formation of Reactive Metabolites -- 4.3.2 Reactive Metabolite Studies: In vitro -- 4.3.3 Reactive Metabolite Studies: In vivo -- 4.3.4 Reactive Metabolite Data Interpretation -- 4.3.5 Metabolite Contribution to Off-Target Toxicities -- 4.4 SAFETY TESTING OF DRUG METABOLITES -- 4.5 SUMMARY -- REFERENCES -- 5: IMPROVING THE PHARMACEUTICAL PROPERTIES OF BIOLOGICS IN DRUG DISCOVERY: UNIQUE CHALLENGES AND ENABLING SOLUTIONS -- 5.1 INTRODUCTION -- 5.2 PHARMACOKINETICS -- 5.3 METABOLISM AND DISPOSITION -- 5.4 IMMUNOGENICITY -- 5.5 TOXICITY AND PRECLINICAL ASSESSMENT -- 5.6 COMPARABILITY -- 5.7 CONCLUSIONS -- REFERENCES -- 6: CLINICAL DOSE ESTIMATION USING PHARMACOKINETIC/PHARMACODYNAMIC MODELING AND SIMULATION -- 6.1 INTRODUCTION -- 6.2 BIOMARKERS IN PK AND PD -- 6.2.1 PK -- 6.2.2 PD -- 6.2.3 Biomarkers -- 6.3 MODEL-BASED CLINICAL DRUG DEVELOPMENT -- 6.3.1 Modeling -- 6.3.2 Simulation -- 6.3.3 Population Modeling -- 6.3.4 Quantitative Pharmacology (QP) and Pharmacometrics -- 6.4 FIRST-IN-HUMAN DOSE -- 6.4.1 Drug Classification Systems as Tools for Development -- 6.4.2 Interspecies and Allometric Scaling -- 6.4.3 Animal Species, Plasma Protein Binding, and in vivo-in vitro Correlation -- 6.5 EXAMPLES -- 6.5.1 First-in-Human Dose -- 6.5.2 Pediatric Dose -- 6.6 DISCUSSION AND CONCLUSION -- REFERENCES -- 7: PHARMACOGENOMICS AND INDIVIDUALIZED MEDICINE -- 7.1 INTRODUCTION -- 7.2 INDIVIDUAL VARIABILITY IN DRUG THERAPY -- 7.3 WE ARE ALL HUMAN VARIANTS -- 7.4 ORIGINS OF INDIVIDUAL VARIABILITY IN DRUG THERAPY -- 7.5 GENETIC POLYMORPHISM OF DRUG TARGETS -- 7.6 GENETIC POLYMORPHISM OF CYTOCHROME P450S.

7.7 GENETIC POLYMORPHISM OF OTHER DRUG METABOLIZING ENZYMES -- 7.8 GENETIC POLYMORPHISM OF TRANSPORTERS -- 7.9 PHARMACOGENOMICS AND DRUG SAFETY -- 7.10 WARFARIN PHARMACOGENOMICS: A MODEL FOR INDIVIDUALIZED MEDICINE -- 7.11 CAN INDIVIDUALIZED DRUG THERAPY BE ACHIEVED? -- 7.12 CONCLUSIONS -- DISCLAIMER -- CONTACT INFORMATION -- REFERENCES -- 8: OVERVIEW OF DRUG METABOLISM AND PHARMACOKINETICS WITH APPLICATIONS IN DRUG DISCOVERY AND DEVELOPMENT IN CHINA -- 8.1 INTRODUCTION -- 8.2 PK-PD TRANSLATION RESEARCH IN NEW DRUG RESEARCH AND DEVELOPMENT -- 8.3 ABSORPTION, DISTRIBUTION, METABOLISM, EXCRETION, AND TOXICITY (ADME/T) STUDIES IN DRUG DISCOVERY AND EARLY STAGE OF DEVELOPMENT -- 8.4 DRUG TRANSPORTERS IN NEW DRUG RESEARCH AND DEVELOPMENT -- 8.5 DRUG METABOLISM AND PK STUDIES FOR NEW DRUG RESEARCH AND DEVELOPMENT -- 8.5.1 Technical Guidelines for PK Studies in China -- 8.5.2 Studies on New Molecular Entity (NME) Drugs -- 8.5.3 PK Calculation Program -- 8.6 STUDIES ON THE PK OF BIOTECHNOLOGICAL PRODUCTS -- 8.7 STUDIES ON THE PK OF TCMS -- 8.7.1 The Challenge in PK Research of TCMs -- 8.7.2 New Concept on PK Markers -- 8.7.3 Identification of Nontarget Components from Herbal Preparations -- 8.8 PK AND BIOAVAILABILITY OF NANOMATERIALS -- 8.8.1 Research and Development of Nanopharmaceuticals -- 8.8.2 Biopharmaceutics and Therapeutic Potential of Engineered Nanomaterials -- 8.8.3 Biodistribution and Biodegradation -- 8.8.4 Doxorubicin Polyethylene Glycol-Phosphatidylethnolamine (PEG-PE) Nanoparticles -- 8.8.5 Micelle-Encapsulated Alprostadil (M-Alp) -- 8.8.6 Paclitaxel Magnetoliposomes -- REFERENCES -- PART B: ADME SYSTEMS AND METHODS -- 9: TECHNICAL CHALLENGES AND RECENT ADVANCES OF IMPLEMENTING COMPREHENSIVE ADMET TOOLS IN DRUG DISCOVERY -- 9.1 INTRODUCTION -- 9.2 "A" IS THE FIRST PHYSIOLOGICAL BARRIER THAT A DRUG FACES -- 9.2.1 Solubility and Dissolution.

9.2.2 GI Permeability and Transporters -- 9.3 "M" IS FREQUENTLY CONSIDERED PRIOR TO DISTRIBUTION DUE TO THE "FIRST-PASS" EFFECT -- 9.3.1 Hepatic Metabolism -- 9.3.2 CYPs and Drug Metabolism -- 9.4 "D" IS CRITICAL FOR CORRECTLY INTERPRETING PK DATA -- 9.4.1 Blood/Plasma Impact on Drug Distribution -- 9.4.2 Plasma Stability -- 9.4.3 PPB -- 9.4.4 Blood/Plasma Partitioning -- 9.5 "E": THE ELIMINATION OF DRUGS SHOULD NOT BE IGNORED -- 9.6 METABOLISM- OR TRANSPORTER-RELATED SAFETY CONCERNS -- 9.7 REVERSIBLE CYP INHIBITION -- 9.7.1 In vitro CYP Inhibition -- 9.7.2 Human Liver Microsomes (HLM) + Prototypical Probe Substrates with Quantification by LC-MS -- 9.7.3 Implementation Strategy -- 9.8 MECHANISM-BASED (TIME-DEPENDENT) CYP INHIBITION -- 9.8.1 Characteristics of CYP3A TDI -- 9.8.2 In vitro Screening for CYP3A TDI -- 9.8.3 Inactivation Rate (kobs) -- 9.8.4 IC50-Shift -- 9.8.5 Implementation Strategy -- 9.9 CYP INDUCTION -- 9.10 REACTIVE METABOLITES -- 9.10.1 Qualitative in vitro Assays -- 9.10.2 Quantitative in vitro Assay -- 9.11 CONCLUSION AND OUTLOOK -- ACKNOWLEDGMENTS -- REFERENCES -- 10: PERMEABILITY AND TRANSPORTER MODELS IN DRUG DISCOVERY AND DEVELOPMENT -- 10.1 INTRODUCTION -- 10.2 PERMEABILITY MODELS -- 10.2.1 PAMPA -- 10.2.2 Cell Models (Caco-2 Cells) -- 10.2.3 P-glycoprotein (Pgp) Models -- 10.3 TRANSPORTER MODELS -- 10.3.1 Intact Cells -- 10.3.2 Transfected Cells -- 10.3.3 Xenopus Oocyte -- 10.3.4 Membrane Vesicles -- 10.3.5 Transgenic Animal Models -- 10.4 INTEGRATED PERMEABILITY-TRANSPORTER SCREENING STRATEGY -- REFERENCES -- 11: METHODS FOR ASSESSING BLOOD-BRAIN BARRIER PENETRATION IN DRUG DISCOVERY -- 11.1 INTRODUCTION -- 11.2 COMMON METHODS FOR ASSESSING BBB PENETRATION -- 11.3 METHODS FOR DETERMINATION OF FREE DRUG CONCENTRATION IN THE BRAIN -- 11.3.1 In vivo Brain PK in Combination with in vitro Brain Homogenate Binding Studies.

11.3.2 Use of CSF Drug Concentration as a Surrogate for Free Drug Concentration in the Brain -- 11.4 METHODS FOR BBB PERMEABILITY -- 11.4.1 In situ Brain Perfusion Assay -- 11.4.2 High-throughput PAMPA-BBB -- 11.4.3 Lipophilicity (LogD7.4) -- 11.5 METHODS FOR PGP EFFLUX TRANSPORT -- 11.6 CONCLUSIONS -- REFERENCES -- 12: TECHNIQUES FOR DETERMINING PROTEIN BINDING IN DRUG DISCOVERY AND DEVELOPMENT -- 12.1 INTRODUCTION -- 12.2 OVERVIEW -- 12.3 EQUILIBRIUM DIALYSIS -- 12.4 ULTRACENTRIFUGATION -- 12.5 ULTRAFILTRATION -- 12.6 MICRODIALYSIS -- 12.7 SPECTROSCOPY -- 12.8 CHROMATOGRAPHIC METHODS -- 12.9 SUMMARY DISCUSSION -- ACKNOWLEDGMENT -- REFERENCES -- 13: REACTION PHENOTYPING -- 13.1 INTRODUCTION -- 13.2 INITIAL CONSIDERATIONS -- 13.2.1 Clearance Mechanism -- 13.2.2 Selecting the Appropriate in vitro System -- 13.2.3 Substrate Concentration -- 13.2.4 Effect of Incubation Time and Protein Concentration -- 13.2.5 Determination of Kinetic Constant Km and Vmax -- 13.2.6 Development of Analytical Methods -- 13.3 CYP REACTION PHENOTYPING -- 13.3.1 Specific Chemical Inhibitors -- 13.3.2 Inhibitory CYP Antibodies -- 13.3.3 Recombinant CYP Enzymes -- 13.3.4 Correlation Analysis for CYP Reaction Phenotyping -- 13.3.5 CYP Reaction Phenotyping in Drug Discovery versus Development -- 13.4 NON-P450 REACTION PHENOTYPING -- 13.4.1 FMOs -- 13.4.2 MAOs -- 13.4.3 AO -- 13.5 UGT CONJUGATION REACTION PHENOTYPING -- 13.5.1 Initial Considerations in UGT Reaction Phenotyping -- 13.5.2 Experimental Approaches for UGT Reaction Phenotyping -- 13.5.3 Use of Chemical Inhibitors for UGTs -- 13.5.4 Correlation Analysis for UGT Reaction Phenotyping -- 13.6 REACTION PHENOTYPING FOR OTHER CONJUGATION REACTIONS -- 13.7 INTEGRATION OF REACTION PHENOTYPING AND PREDICTION OF DDI -- 13.8 CONCLUSION -- REFERENCES -- 14: FAST AND RELIABLE CYP INHIBITION ASSAYS -- 14.1 INTRODUCTION.

14.2 CYP INHIBITION ASSAYS IN DRUG DISCOVERY AND DEVELOPMENT.