Souzan B Yanni

Translational Admet for Drug Therapy

Principles, Methods, and Pharmaceutical Applications

• Gebundenes Buch

Produktbeschreibung

Serving as a practical handbook about ADMET for drug therapy, this book presents effective technologies, methods, applications, data interpretation, and decision-making tactics for pharmaceutical and preclinical scientists. Chapters cover case studies and in vivo, in vitro, and computational tools for drug discovery and development, with new translational approaches to clinical drug investigations in various human populations. * Illustrates ADME properties, from bedside to bench and bench to bedside, for the design of safe and effective medicine in human populations * Provides examples that demonstrate the integration of in vitro, in vivo, and in silico data to address human PKPD and TKTD and help determine the proper therapeutic dosage * Presents successful tools for evaluating drugs and covers current translational ADMET with regulatory guidelines * Offers a hands-on manual for researchers and scientists to design and execute in vitro, in silico, preclinical, and clinical studies * Includes discussion of IND / NDA filing and drug labeling to support drug registration and approval

Produktdetails

• Verlag: John Wiley & Sons / Wiley
• Seitenzahl: 352
• Erscheinungstermin: 12. Oktober 2015
• Englisch
• Abmessung: 240mm x 161mm x 24mm
• Gewicht: 698g
• ISBN-13: 9781118838273
• ISBN-10: 1118838270
• Artikelnr.: 42835416

Autorenporträt

Souzan B. Yanni, PhD, is Founder and President of DMPK Consultants, Inc., which leads ADME/PK in support of preclinical and clinical investigations for of pharmaceutical and biotech companies. She has over 20 years of hands-on leadership experience in planning, executing, and overseeing drug discovery and early development for therapeutic programs with national and international pharmaceutical companies, biotech groups, and CROs. Dr. Yanni possesses a PhD in Pharmaceutical Sciences, MS in Biochemistry, and BS in Chemistry. She is the author of several peer-reviewed articles, review articles, and book chapters on ADMET/PK as well as an external reviewer / editor for other journals.

Inhaltsangabe

Contributors xv Preface xvii Acknowledgement xxi 1 Translational Concept
and Determination of Drug Absorption 1 1.1 Drug Absorption, Mechanism, and
its Impact on Drug Bioavailability, Drug Disposition, and Drug Safety 1
1.1.1 Drug Absorption and Oral Bioavailability 2 1.1.2 Contribution of
Intestinal Drug Transporters and Drug-Metabolizing Enzymes on Extent of
Absorption and Mechanism 4 1.1.2.1 Intestinal Transporters 4 1.1.2.2 The
Impact of Intestinal Metabolism on Drug Absorption 8 1.2 Effect of
Physiochemical Property-Related Factors on Drug Absorption 9 1.2.1
Lipophilicity, Solubility and Dissolution, and Permeability 9 1.2.1.1
Lipophilicity 9 1.2.1.2 Solubility 11 1.2.1.3 Permeability 12 1.3 Effect of
GI-Physiological Factors and Patient Condition on Drug Absorption 14 1.3.1
Effect of pH, Intestinal Surface Area, Gastric Emptying, Transient Time,
and Bile Acid 14 1.3.1.1 Effect of pH and Surface Area 14 1.3.1.2 Effect of
Gastric Emptying and Intestinal Transit Time 17 1.3.1.3 Effect of Bile and
Bile Salts 17 1.3.2 Impact of Age and Disease State on Drug Absorption 18
1.3.2.1 Drug Absorption in Pediatric Populations 18 1.3.2.2 Drug Absorption
in Disease State 19 1.4 Effect of Food and Formulation on Drug Absorption
20 1.4.1 Effect of Food 20 1.4.2 Formulation Effect 21 1.4.3 The BCS in
Relation to Intestinal Absorption 22 1.5 Translational Approaches to
Determine Drug Absorption in Clinical Studies 24 1.5.1 Cellular Intestinal
Model 24 1.5.2 In Vitro Artificial Membrane 24 1.5.3 Non-In Vitro Models:
In Situ and In Vivo 25 References 27 2 Distribution: Principle, Methods,
and Applications 37 2.1 Introduction: Drug Distribution in Relation to Drug
Disposition in Humans 37 2.2 Influence of Drug-Related Physiochemical
Factors on Drug Distribution 39 2.3 Influence of Physiological Factors on
Drug Distribution 42 2.3.1 Effect of BodyWater Content, Perfusion, and
Diffusion on Drug Distribution 43 2.3.1.1 Effect of Body Water 43 2.3.1.2
Effect of Perfusion and Diffusion on Drug Distribution 44 2.4 Plasma
Protein Binding 45 2.4.1 Effect of Biomedical Conditions: Disease State and
Pregnancy 45 2.4.2 Protein Binding as a Function of Age 46 2.5 Role of Drug
Transporters in Drug Distribution 47 2.5.1 Drug Distribution as a Function
of Efflux Drug Transporters 48 2.6 Translational Methods and Approaches in
Determining Drug Distribution 49 2.6.1 In Vitro Methods for Determination
of Protein Binding 49 2.6.2 In Vivo Protein Binding Studies in Preclinical
Animals and Humans 51 2.6.2.1 Using Radiolabeled Drugs 51 2.6.2.2 Applying
Advanced Translational Tools for Determining Drug Distribution in Humans 52
2.6.3 Assess Drug Distribution from Transporter Studies 53 2.6.3.1 Use of
Membrane Vesicles 53 2.6.3.2 Use Cultured-Cell Based Assay 53 2.7 Impact of
Drug Distribution in Drug Disposition DDI in Clinic 55 References 58 3
Metabolism: Principle, Methods, and Applications 63 3.1 Introduction: An
Overview on Drug Metabolism in Relation to Clearance--Mediated by Phase I,
Phase II, and Phase III Drug-Metabolizing Enzymes 63 3.2 Common Phase I,
II, and III Drug Metabolism Reactions 69 3.2.1 Phase I Drug Metabolism 69
3.2.1.1 Oxidation Reaction 70 3.2.2 Phase II Conjugation Biotransformation
Reactions 71 3.2.2.1 UDP-Glucuronosyltransferase (UGT) 71 3.2.2.2 Other
Conjugation Reactions: Sulfonyltransferase, Glutathione-S-Transferases,
Methyl Transferases, and N-Acetyl Transferases 75 3.2.3 Phase III
Metabolism 77 3.2.4 Localization of Drug Metabolism in Organ Cells 78 3.3
Metabolic Clearance as a Critical Factor Influencing Drug Action and Safety
78 3.3.1 Effect of Physiological Factors on Drug Metabolism-Mediated Drug
Clearance 80 3.3.1.1 Protein Binding 81 3.3.1.2 Hepatic Blood Flow (QH) 82
3.3.1.3 Liver Size Relative to Body Weight 82 3.3.1.4 Milligram Microsomal
Protein per Gram of Liver 82 3.3.2 Role of Drug Transporters 82 3.3.3
Effect of Age on Drug Metabolism and Clearance 84 3.3.4 Effect of Hormones
on Metabolic Clearance and Gender Difference in Drug Metabolism 86 3.3.5
Effects of Disease on Drug Metabolism 86 3.3.6 Genetic Polymorphism and
Ethnic Variability Effect on Metabolic Clearance 87 3.4 Species Differences
in Drug Metabolism 89 3.5 Translational Technologies and Methodologies and
Regulatory Recommendation for Drug Metabolism 91 3.5.1 In Vitro Models of
Drug Metabolism 92 3.5.1.1 Single-cDNA Expressed Enzymes 92 3.5.1.2
Subcellular Fractions 93 3.5.1.3 Cellular Systems 94 3.5.2 In Vivo Models
of Drug Metabolism 95 3.5.2.1 Preclinical Animal Studies 95 3.5.2.2
Genetically Modified Animal/Chimeric Mouse Model/Ex Vivo/In Situ Organ
Perfusion 96 References 98 4 Excretion: Principle, Methods, and
Applications for Better Therapy 111 4.1 Outline of Drug Excretion and
Mechanisms 111 4.2 Excretion of Drugs in Humans as Function of Drug
Transporters 112 4.2.1 Biliary and Renal Excretion 112 4.2.1.1 Biliary
Excretion 113 4.2.1.2 Renal Excretion 115 4.2.2 Drug Transporter Function
in Renal Excretion 118 4.3 Translational Tools to Determine the Biliary and
Renal Clearance 119 4.3.1 In Vitro Methods in Determination of Biliary
Clearance 119 4.3.2 In Vitro Methods in Determination of Renal Clearance
122 4.3.3 In Vivo Methods in Determination of Biliary and Renal Clearances
125 4.3.3.1 MBSs in Humans 125 4.3.4 In Vivo Model to Study Excretion and
Toxicity: Chimeric Mice with Humanized Liver 128 4.4 Impairment of Drug
Elimination 128 4.4.1 Hepatic Impartment: Cholestasis 128 4.4.2 Renal
Impartment: Chronic Kidney Disease (CKD) 130 References 133 5 Drug-Drug
Interaction: From Bench to Drug Label 139 5.1 Introduction: The Impact of
Drug-Drug Interaction on Drug Disposition and Drug Safety 139 5.2 DDIs
Implicated with Drug-Metabolizing Enzymes (DMEs) and Drug Metabolism 141
5.2.1 DDI Mediated by P450 Inhibition 141 5.2.1.1 In Vitro P450 Inhibition
Models and Methodologies 142 5.2.1.2 Translating In Vitro P450 Inhibition
Data to Clinical DDI 144 5.2.2 Mechanism-Based P450 Inactivation DDI 146
5.2.2.1 Translating the In Vitro Information to Clinical Pharmacology
Investigation 147 5.2.3 DDI Mediated by P450 Induction 152 5.2.3.1 In Vitro
P450 Induction Models and Methodologies 152 5.2.3.2 Translating In Vitro
P450 Induction Data to Clinical DDI 156 5.3 Incidence of DDI Due to Drug
Transporters 158 5.3.1 DDI-Mediated Uptake Transporters 159 5.3.2
DDI-Mediated Efflux Transporters 162 5.4 Clinical DDI 163 5.4.1 DDI in
Pediatric Patients 164 5.4.2 Clinical DDI Study Designs 166 5.4.3
Statistical Approach in Clinical DDI Studies 168 5.5 Conclusion 169
References 169 6 General Toxicology: Principle, Methods, and Applications
179 6.1 Introduction: The History of Toxicology 179 6.2 The Multifaceted
Field of Toxicology 183 6.2.1 Various Disciplines in Toxicology 183 6.2.2
Principles of Toxicology 184 6.3 Characteristics of Toxicants, Toxins, and
Exposures 184 6.3.1 Use Classes 185 6.3.2 Characteristics of Exposure 186
6.3.3 Length of Exposure 186 6.3.4 Routes of Exposure 187 6.3.5 Dose
Response 187 6.3.6 Tolerance 188 6.4 Adverse Drug Reactions: Idiosyncratic
and Drug-Induced Liver Injury (DILI) 188 6.4.1 Idiosyncratic Drug Reactions
(IDRs) 188 6.4.2 Drug-Induced Liver Injury 190 6.5 In Vitro Determination
of Reactive Metabolite Formation, Oxidative Stress, Mitochondrial Damage,
and Nephrotoxicity 193 6.6 Present and Future for Assessing Toxicity in
Drug Discovery and Development 197 References 200 7 Toxicokinetics and
Toxicity Testing in Drug Development 205 7.1 Introduction: Toxicokinetics
and Its Relationship with Pharmacokinetics and ADME in Preclinical
Development 205 7.2 Types of Preclinical Dosing that Support Toxicokinetics
206 7.2.1 Single-Dose Toxicity Studies 207 7.2.2 Repeated-Dose Toxicity
Studies 207 7.3 Pharmacokinetic Parameters in Support of Toxicokinetic
Assessments 209 7.3.1 Area Under the Curve (AUC) 209 7.3.2 Maximum Plasma
Concentration (Cmax) and Time of Maximum Concentration (Tmax) 210 7.3.3
Clearance 210 7.3.4 Apparent Volume of Distribution (Vd) 211 7.3.5 Apparent
Volume of Distribution at Steady State (Vdss) 211 7.3.6 Half-Life (t1¿M2)
212 7.3.7 Bioavailability (F%) 212 7.4 Genotoxicity, Oncogenicity,
Reproductive Toxicity versus Toxicogenomics and Biomarkers in Preclinical
Species 213 7.4.1 Genotoxicity Studies 213 7.4.2 Carcinogenicity
(Oncogenicity) Studies 214 7.4.3 Reproductive Toxicity Studies 214 7.4.4
Toxicogenomics Studies 215 7.5 Drug Metabolism and Drug Related-Toxicities
215 References 218 8 PBPK Modeling and In Silico Prediction for ADME and
Drug-Drug Interaction 221 8.1 Introduction: Computational Assessment of
ADME and Drug-Drug Interaction (DDI) within Pharmaceutical R&D Paradigm 221
8.2 PBPK Models for ADMET and DDI 223 8.2.1 General PBPK Model and
Physiological Parameters that Affect Drug Disposition 223 8.2.2 Simple
Organ-Based PBPK Models 227 8.2.2.1 PBPK for Liver 227 8.2.2.2 Whole-Body
PBPK Models 229 8.2.3 PBPK Model for DDI 230 8.2.4 PBPK and Genetic
Polymorphism 232 8.3 In Silico Prediction of ADMET 232 8.3.1 Significance
of Using In Silico Modeling: In Silico versus PBPK Modeling 233 8.3.2
Methods for In Silico ADMET Prediction 233 8.3.2.1 Data Modeling 233
8.3.2.2 Molecular Modeling 234 8.4 Applications of In Silico Models in
ADME, DDI, and Drug Toxicity 234 8.4.1 Prediction of the Rate of Metabolism
235 8.4.2 DDI of Metabolism 235 8.4.3 Identifying Substrates for
Transporters 235 References 236 9 Translational Tools toward Better Drug
Therapy in Human Populations 241 9.1 Introduction: Translational ADMET and
its Therapeutic Value 241 9.2 Translational Bioinformatics and Biomarkers:
Utilization for Better Drug Therapy 244 9.2.1 In Cancer 245 9.2.2 In
Chronic Kidney Disease (CKD) 245 9.2.3 Role of Biomarkers in CNS 246 9.2.4
Biomarkers in Diabetes and Their Role in AD 247 9.3 Genomics and
Pharmacogenomics in Translational ADMET 249 9.3.1 Influence of
Pharmacogenomics on Drug Metabolism-Mediated Drug Development 250 9.3.2
Influence of Pharmacogenomics on Drug Transporter-Mediated Drug Development
255 9.4 Translational ADMET, Approaches and Tools 257 9.4.1 From Bedside to
Bench to Bedside: POC Investigations 257 9.4.1.1 Individualized Antifungal
Drug Therapy in Pediatric Patients 257 9.4.1.2 "From Bedside to Bench" in
Rare Pediatric Leukemia 261 9.4.2 From Juvenile Animal Model to Human Adult
262 9.4.3 Use of Chimeric Rodents with Humanized Liver as a Translation
Model in Bridging the Gap between Preclinical and Clinical Trials in ADMET
263 9.5 Scaling of PK in Prediction of Human PK and Dosing 264 9.5.1 From
Adult PK to Pediatric: Calculation of In Vivo CL in Children 264 9.5.2 From
Animal PK to Human Dose 268 9.5.2.1 CL and PK/TK Modeling in Predicting
Clinical Dose 270 References 271 10 Phase 1-Phase 3 Clinical Studies,
Procedures, Responsibilities, and Documentation 277 10.1 Introduction: What
is Clinical Investigation? Goals, Utility, and Processes of Four Phases in
Clinical Drug Development 277 10.2 General Clinical Study Design:
Enrollment, Responsibilities, and Documentation 282 10.2.1 Clinical Study
Protocol 283 10.2.2 Patient Selection and Eligibility Criteria 284 10.2.3
Typical Study Design Features 285 10.2.3.1 Randomized Clinical Trials 285
10.2.3.2 Blinding versus Masking 286 10.2.4 Responsibilities: IRBs,
Regulatory Authorities, Sponsor, PI, Patients 287 10.2.4.1 Institutional
Review Boards 287 10.2.4.2 Role of Regulatory Agencies 287 10.2.4.3
Responsibility of Sponsor 289 10.3 Integration of Clinical Trials with
Preclinical Absorption, Distribution, Metabolism, and Excretion (ADME),
Drug-Drug Interaction (DDI), and Pharmacogenomics in Investigating 290
10.3.1 Assessment of DDI and Disposition 290 10.3.2 Mechanism Underlying
Drug Therapy (Aromatase Inhibitors) for Breast Cancer 295 10.3.3 Mechanism
Underlying Drug Therapy (Metformin) for Type 2 Diabetes 297 10.4 Clinical
Pharmacology Studies of Special Populations 298 10.4.1 Pediatrics and
Geriatrics 299 10.4.2 Renal Impaired 300 10.4.3 Hepatic Impaired 300 10.4.4
Genetic Polymorphic Populations 301 10.4.5 Different Ethnic Populations 302
References 302 11 Regulatory Submission: MIST and Drug Safety Assessment
307 11.1 Drug Development and Approval Processes According to the Food and
Drug Administration (FDA), European Medicines Agency (EMA), and Other
Regulatory Authorities 307 11.2 Studies Required for IND and NDA 309 11.2.1
Types of INDs, Types of Information, and Timelines 309 11.2.1.1 Chemistry
and Manufacturing Control 309 11.2.1.2 Pharmacology/Toxicology 310 11.2.1.3
Pharmacology and Drug Distribution (21 CFR 312.23(a)(8)(I)) 310 11.2.1.4
Toxicology Data Present Regulations (21 CFR 312.23(a)(8)(ii)(a)) 310
11.2.1.5 Medical Review 310 11.2.1.6 Safety Review 311 11.2.1.7 Statistical
Review 311 11.2.1.8 Timelines and Clinical Hold Decision 311 11.2.1.9
Notify Sponsor 311 11.2.2 Metabolites in Safety Testing (MIST)
Regulation--Safety Assessments in Humans 311 11.2.3 Highlights of the AAPS
2013 MIST Symposium 314 11.2.3.1 ICH M3(R2) and Metabolite Issues 314
11.2.3.2 Early Assessment of MIST Liability of a Clinical Drug Candidate
without the Use of Radiolabel 316 11.2.3.3 MIST: How Do We Deal with
Surprises? 316 11.2.3.4 A Simple LC-MS/MS Method for Evaluating MIST
Coverage 316 11.3 Drug Labeling and Black Box Warning 317 11.3.1 Sections
Included in Drug Label 319 11.3.1.1 Drug Dosing 319 11.3.1.2 Age in Drug
Labeling 319 11.3.1.3 Renal and Hepatic Impairment 320 11.3.1.4 Drug
Metabolism 320 11.3.1.5 Genetic Polymorphism, Ethnic Differences 322
References 323 Index 327