{"product_id":"putting-pharmacokinetics-and-pharmacodynamics-to-work-in-drug-discovery-isbn-9781119650201","title":"Putting Pharmacokinetics and Pharmacodynamics to Work in Drug Discovery","description":"\u003cp\u003e\u003cb\u003eDevelop drugs with a greater understanding of their physiological effects\u003c\/b\u003e \u003c\/p\u003e\u003cp\u003ePharmaceutical scientists in the fields of pharmacokinetics and pharmacodynamics study how drugs behave in the body and how they reach their site of action to exert their intended pharmacological activities. Drug discovery stands to benefit enormously from the timely application of pharmacokinetics and pharmacodynamics in order to make informed decisions and solve practical problems. \u003c\/p\u003e\u003cp\u003e\u003ci\u003ePutting Pharmacokinetics and Pharmacodynamics to Work in Drug Discovery\u003c\/i\u003e bridges between scientific concepts and practical industrial practice by bringing these principles to bear on every stage of the drug discovery process. Beginning with target identification and moving through each subsequent decision point including high throughput screening, hit-to-lead, lead optimization and candidate selection. The book offers a comprehensive guide to using various analytical tools including modeling and AI\/ML for minimizing attrition, reducing costs, and more. The result is an invaluable tool in developing smarter and more effective drug discovery processes. \u003c\/p\u003e\u003cp\u003e\u003ci\u003ePutting Pharmacokinetics and Pharmacodynamics to Work in Drug Discovery\u003c\/i\u003e readers will also find: \u003c\/p\u003e\u003cul\u003e\n\u003cli\u003eA work designed to make scientific principles accessible to pharmaceutical scientists in diverse areas, not just pharmacokinetists or DMPK scientists\u003c\/li\u003e\n\u003cli\u003eIndustrial examples, both positive and negative, showing pharmacokinetic and pharmacodynamic principles at work\u003c\/li\u003e\n\u003cli\u003eExercises throughout the book to encourage holistic and integrated thinking\u003c\/li\u003e\n\u003c\/ul\u003e \u003cp\u003e\u003ci\u003ePutting Pharmacokinetics and Pharmacodynamics to Work in Drug Discovery\u003c\/i\u003e is ideal for any researchers or professionals involved in drug discovery and development, including medicinal chemists, biopharmaceutics scientists, clinicians, project leaders, and many others. \u003c\/p\u003e\u003cp\u003ePreface xiii\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart I Optimizing Pharmacokinetics in Discovery 1\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e1 The Importance of Pharmacokinetics in Early Drug Discovery 3\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e1.1 PK as a Surrogate for Efficacy 3\u003c\/p\u003e \u003cp\u003e1.2 The Many Faces of Pharmacokineticists 6\u003c\/p\u003e \u003cp\u003e1.3 The Criteria for Good PK of a Therapeutically Useful Drug 9\u003c\/p\u003e \u003cp\u003e1.4 The Goals of Early Discovery 10\u003c\/p\u003e \u003cp\u003eReferences 13\u003c\/p\u003e \u003cp\u003e\u003cb\u003e2 In Search of “Good” Pharmacokinetics 15\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e2.1 Describing the Concentration-time Profile 16\u003c\/p\u003e \u003cp\u003e2.2 Half-life (T \u003csub\u003e1\/2\u003c\/sub\u003e) 20\u003c\/p\u003e \u003cp\u003e2.3 Area Under the Curve (AUC) 24\u003c\/p\u003e \u003cp\u003e2.4 Biphasic PK Parameters 28\u003c\/p\u003e \u003cp\u003e2.5 Constant Intravenous Infusion PK 32\u003c\/p\u003e \u003cp\u003e2.6 Extravascular PK 33\u003c\/p\u003e \u003cp\u003e2.7 Repeat-dose PK 37\u003c\/p\u003e \u003cp\u003e2.8 Using Secondary PK Parameters to Guide Compound Selection 44\u003c\/p\u003e \u003cp\u003e2.9 Practical Considerations of Conducting In Vivo PK Studies 49\u003c\/p\u003e \u003cp\u003eReferences 52\u003c\/p\u003e \u003cp\u003e\u003cb\u003e3 Linking Descriptive Pharmacokinetics to Underlying ADME Processes 55\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e3.1 The Body as Compartments: Exponential Time Courses Explained 57\u003c\/p\u003e \u003cp\u003e3.2 Relating Descriptive PK Parameters to the Underlying ADME Process 66\u003c\/p\u003e \u003cp\u003e3.3 Using Primary PK Parameters to Identify ADME Liabilities 74\u003c\/p\u003e \u003cp\u003e3.4 Volume of Distribution and Clearance for Compounds with Biphasic PK 77\u003c\/p\u003e \u003cp\u003e3.5 Conversion Between Blood, Plasma, and Unbound PK Parameters 82\u003c\/p\u003e \u003cp\u003e3.6 Ranges of PK Parameters 85\u003c\/p\u003e \u003cp\u003e3.7 Using Primary PK Parameters to Guide Compound Selection 87\u003c\/p\u003e \u003cp\u003e3.8 Linking Primary PK Parameters to Intrinsic Compound Properties 97\u003c\/p\u003e \u003cp\u003eReferences 98\u003c\/p\u003e \u003cp\u003e\u003cb\u003e4 Mechanistic Basis of Distribution 101\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e4.1 Overview of Distribution Process 101\u003c\/p\u003e \u003cp\u003e4.2 Factors Affecting Extent of Distribution 101\u003c\/p\u003e \u003cp\u003e4.3 Using Volume of Distribution to Guide Drug Design and Selection 109\u003c\/p\u003e \u003cp\u003e4.4 Mechanistic Basis of Biphasic PK 112\u003c\/p\u003e \u003cp\u003e4.5 Using Rate of Distribution to Guide Lead Optimization 121\u003c\/p\u003e \u003cp\u003e4.6 Mechanistic Basis of Plasma Protein Binding 122\u003c\/p\u003e \u003cp\u003eReferences 124\u003c\/p\u003e \u003cp\u003e\u003cb\u003e5 Mechanistic Basis of Clearance 127\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e5.1 Liver Metabolism as the Primary Clearance Pathway 128\u003c\/p\u003e \u003cp\u003e5.2 Mechanistic Basis of Hepatic Metabolic Clearance 129\u003c\/p\u003e \u003cp\u003e5.3 Applications of Clearance Concept in Drug Discovery 136\u003c\/p\u003e \u003cp\u003e5.4 Other Routes of Elimination 144\u003c\/p\u003e \u003cp\u003e5.5 Identifying the Rate-limiting Clearance Mechanisms 151\u003c\/p\u003e \u003cp\u003e5.6 Drug–Drug Interaction and Metabolism Considerations 152\u003c\/p\u003e \u003cp\u003eReferences 153\u003c\/p\u003e \u003cp\u003e\u003cb\u003e6 Mechanistic Basis of Absorption 159\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e6.1 Overview of the Absorption Process 160\u003c\/p\u003e \u003cp\u003e6.2 Factors Affecting Fraction Absorbed 161\u003c\/p\u003e \u003cp\u003e6.3 First Pass Extraction 169\u003c\/p\u003e \u003cp\u003e6.4 Interplay Between Absorption, First-pass Elimination, and Transporters 173\u003c\/p\u003e \u003cp\u003e6.5 Applications of Absorption Concepts in Drug Discovery 174\u003c\/p\u003e \u003cp\u003e6.6 Effect of Food on Oral Bioavailability 181\u003c\/p\u003e \u003cp\u003e6.7 Lymphatic Absorption of Lipophilic Compounds 182\u003c\/p\u003e \u003cp\u003eReferences 184\u003c\/p\u003e \u003cp\u003e\u003cb\u003e7 Integrated Pharmacokinetic Analysis in Discovery 189\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e7.1 Integration of PK Concepts: A Road Map 189\u003c\/p\u003e \u003cp\u003e7.2 Is Plasma Protein Binding Important? 194\u003c\/p\u003e \u003cp\u003e7.3 How Potent Is Enough to Elicit Efficacy In Vivo? 197\u003c\/p\u003e \u003cp\u003e7.4 Compounds\/Series Selection 199\u003c\/p\u003e \u003cp\u003e7.5 Drug Design 207\u003c\/p\u003e \u003cp\u003e7.6 Identify ADME Liabilities 208\u003c\/p\u003e \u003cp\u003e7.7 Study Design 213\u003c\/p\u003e \u003cp\u003e7.8 Physiologically Based Pharmacokinetic (PBPK) Modeling 220\u003c\/p\u003e \u003cp\u003eReferences 229\u003c\/p\u003e \u003cp\u003e\u003cb\u003e8 Pharmacokinetics of Therapeutic Antibodies and Derivatives 235\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e8.1 General PK Characteristics of mAbs 237\u003c\/p\u003e \u003cp\u003e8.2 Absorption of Monoclonal Antibodies 239\u003c\/p\u003e \u003cp\u003e8.3 Distribution of Monoclonal Antibodies 241\u003c\/p\u003e \u003cp\u003e8.4 Clearance of Monoclonal Antibodies 244\u003c\/p\u003e \u003cp\u003e8.5 PBPK Modeling for Monoclonal Antibodies 246\u003c\/p\u003e \u003cp\u003e8.6 PK Screening and Optimization of Monoclonal Antibodies 250\u003c\/p\u003e \u003cp\u003eReferences 253\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart 2 From Pharmacokinetics to Efficacy 259\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e9 The Importance of Pharmacodynamics in Early Drug Discovery 261\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e9.1 The PK-PD Disconnect 262\u003c\/p\u003e \u003cp\u003e9.2 The Three Pillars of PD 264\u003c\/p\u003e \u003cp\u003e9.3 Experimental Approaches for Studying Pharmacological Effects 267\u003c\/p\u003e \u003cp\u003eReferences 269\u003c\/p\u003e \u003cp\u003e\u003cb\u003e10 Reaching the Site of Action 271\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e10.1 Free Drug Hypothesis 272\u003c\/p\u003e \u003cp\u003e10.2 Asymmetry in Unbound Tissue and Systemic Concentration 273\u003c\/p\u003e \u003cp\u003e10.3 Time-course of Unbound Concentration in Target Tissue 278\u003c\/p\u003e \u003cp\u003e10.4 Tissue Disposition Considerations in Drug Discovery 286\u003c\/p\u003e \u003cp\u003e10.5 Target Organs with Complex Structures 295\u003c\/p\u003e \u003cp\u003e10.6 When Systemic PK Is Not the Main Driver for Tissue Exposure 299\u003c\/p\u003e \u003cp\u003e10.7 Tissue Disposition for Therapeutic Antibodies 303\u003c\/p\u003e \u003cp\u003eReferences 304\u003c\/p\u003e \u003cp\u003e\u003cb\u003e11 Hitting a Moving Target 311\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e11.1 Concentration-response Relationships 311\u003c\/p\u003e \u003cp\u003e11.2 Receptor Kinetics Theory 315\u003c\/p\u003e \u003cp\u003e11.3 Agonism 317\u003c\/p\u003e \u003cp\u003e11.4 Antagonism 319\u003c\/p\u003e \u003cp\u003e11.5 Slow Association and Disassociation 320\u003c\/p\u003e \u003cp\u003e11.6 Target Turnover 322\u003c\/p\u003e \u003cp\u003e11.7 Irreversible Inactivation 325\u003c\/p\u003e \u003cp\u003e11.8 Proteolysis Targeting Chimeras (PROTACs) 329\u003c\/p\u003e \u003cp\u003e11.9 Bisubstrate Kinetics 330\u003c\/p\u003e \u003cp\u003e11.10 Implications to Toxicological Effects 332\u003c\/p\u003e \u003cp\u003e11.11 Monoclonal Antibodies Target Engagement 333\u003c\/p\u003e \u003cp\u003eReferences 337\u003c\/p\u003e \u003cp\u003e\u003cb\u003e12 The Tangled Web of Pharmacology 343\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e12.1 Fast Responding Processes 346\u003c\/p\u003e \u003cp\u003e12.2 Slow Turnover Processes 346\u003c\/p\u003e \u003cp\u003e12.3 Multistage Processes 354\u003c\/p\u003e \u003cp\u003e12.4 Activation of Precursor 358\u003c\/p\u003e \u003cp\u003e12.5 Tolerance and Resistance 363\u003c\/p\u003e \u003cp\u003e12.6 Cell Growth and Death 367\u003c\/p\u003e \u003cp\u003e12.7 Importance of Response Duration in Determining PK Endpoints 369\u003c\/p\u003e \u003cp\u003e12.8 Monoclonal Antibodies 369\u003c\/p\u003e \u003cp\u003e12.9 Complex and Novel Systems 371\u003c\/p\u003e \u003cp\u003e12.10 Toxicodynamics 371\u003c\/p\u003e \u003cp\u003eReferences 372\u003c\/p\u003e \u003cp\u003e\u003cb\u003e13 Pharmacodynamics-informed Drug Discovery 375\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e13.1 Selection of Target, Modality, and Mode of Action 376\u003c\/p\u003e \u003cp\u003e13.2 Compound Screening 378\u003c\/p\u003e \u003cp\u003e13.3 Compound Optimization 384\u003c\/p\u003e \u003cp\u003e13.4 Virtual Screening and Drug Design 385\u003c\/p\u003e \u003cp\u003e13.5 Design and Interpretation of Pharmacology Studies 387\u003c\/p\u003e \u003cp\u003e13.6 Model-informed Drug Discovery 395\u003c\/p\u003e \u003cp\u003eReferences 410\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart III Picking the Right Human Dose 413\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e14 Human Dose Prediction: An Overview 415\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eReferences 420\u003c\/p\u003e \u003cp\u003e\u003cb\u003e15 Predicting Human Systemic Pharmacokinetics 421\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e15.1 Predicting Human Volumes of Distribution and Clearance 421\u003c\/p\u003e \u003cp\u003e15.2 Predicting Human Oral Bioavailability 432\u003c\/p\u003e \u003cp\u003e15.3 Predicting the Concentration-time Profile 437\u003c\/p\u003e \u003cp\u003e15.4 When Prediction of Human Systemic PK Is Unimportant 439\u003c\/p\u003e \u003cp\u003e15.5 Predicting Human PK for Monoclonal Antibodies 441\u003c\/p\u003e \u003cp\u003eReferences 442\u003c\/p\u003e \u003cp\u003e\u003cb\u003e16 Predicting Human Pharmacodynamics 447\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e16.1 Species Difference in Tissue Disposition 448\u003c\/p\u003e \u003cp\u003e16.2 Species Differences in Target Engagement 449\u003c\/p\u003e \u003cp\u003e16.3 Species Differences in the Behaviors of Pharmacology 456\u003c\/p\u003e \u003cp\u003eReferences 468\u003c\/p\u003e \u003cp\u003e\u003cb\u003e17 Integrated PK\/PD Approaches to Human Dose Prediction 473\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e17.1 A Simple Example of Starting First-in-human Dose Calculation 475\u003c\/p\u003e \u003cp\u003e17.2 PK\/PD Model-based MABEL Determination 478\u003c\/p\u003e \u003cp\u003e17.3 Evaluating Data Quality 493\u003c\/p\u003e \u003cp\u003e17.4 Quantifying the Impact of Uncertainty on Decisions 499\u003c\/p\u003e \u003cp\u003eReferences 504\u003c\/p\u003e \u003cp\u003eAppendix A: In Vitro ADME Assays 507\u003c\/p\u003e \u003cp\u003eA.1 Permeability 507\u003c\/p\u003e \u003cp\u003eA.2 Solubility and Dissolution 508\u003c\/p\u003e \u003cp\u003eA.3 Plasma Protein Binding 509\u003c\/p\u003e \u003cp\u003eA.4 Blood-to-plasma Ratio, ​B : P​ 510\u003c\/p\u003e \u003cp\u003eA.5 Tissue Partitioning 510\u003c\/p\u003e \u003cp\u003eA.6 Transporters 510\u003c\/p\u003e \u003cp\u003eA.7 Intrinsic Metabolic Clearance (Stability) 511\u003c\/p\u003e \u003cp\u003eA.8 CYP450 Phenotyping 511\u003c\/p\u003e \u003cp\u003eA.9 CYP450 Inhibition 512\u003c\/p\u003e \u003cp\u003eA.10 CYP450 Time-dependent Inhibition 513\u003c\/p\u003e \u003cp\u003eReferences 513\u003c\/p\u003e \u003cp\u003eAppendix B: QSAR and QSPR Models 515\u003c\/p\u003e \u003cp\u003eB. 1 What Are QSAR and QSPR Models? 515\u003c\/p\u003e \u003cp\u003eB. 2 Model-building Process 515\u003c\/p\u003e \u003cp\u003eB. 3 Molecular Descriptors 516\u003c\/p\u003e \u003cp\u003eB. 4 Global Versus Local Models 516\u003c\/p\u003e \u003cp\u003eB. 5 Types of Models 516\u003c\/p\u003e \u003cp\u003eB. 6 Validation and Prediction 517\u003c\/p\u003e \u003cp\u003eReferences 517\u003c\/p\u003e \u003cp\u003eAppendix C: Methods for Monitoring Tissue Concentrations 519\u003c\/p\u003e \u003cp\u003eAppendix D: Anatomical and Physiological Parameters 521\u003c\/p\u003e \u003cp\u003eD.1 Blood Flows 521\u003c\/p\u003e \u003cp\u003eD.2 Volumes of Organs and Body Fluids 522\u003c\/p\u003e \u003cp\u003eD.3 Intestinal Physiology 523\u003c\/p\u003e \u003cp\u003eD.4 Miscellaneous Properties 523\u003c\/p\u003e \u003cp\u003eReferences 524\u003c\/p\u003e \u003cp\u003eAppendix E: Useful Equations 525\u003c\/p\u003e \u003cp\u003eE. 1 Calculating Secondary PK Parameters from Concentration-time Data 525\u003c\/p\u003e \u003cp\u003eE. 2 Calculating Primary PK Parameters from Secondary PK Parameters 526\u003c\/p\u003e \u003cp\u003eE. 3 Conversions Between Plasma, Blood, and Unbound PK Parameters 527\u003c\/p\u003e \u003cp\u003eE. 4 Calculating Primary PK Parameters from In Vitro or In Silico Data 527\u003c\/p\u003e \u003cp\u003eE. 5 Calculating the Concentration-time Profile from Primary PK Parameters 528\u003c\/p\u003e \u003cp\u003eSymbols and Abbreviations 531\u003c\/p\u003e \u003cp\u003eIndex 537\u003c\/p\u003e  \\\u003cp\u003e\u003cb\u003eEmile P. Chen, PhD,\u003c\/b\u003e was Director of Modeling and Translational Biology at GlaxoSmithKline. He has over 30 years of industrial experience with expertise in pharmacokinetics, pharmacodynamics, mathematical modeling (PBPK, PK\/ PD and QSP), and AI\/ML and has designed numerous interactive workshops focused on the applications of these subjects in drug discovery.   \u003c\/p\u003e\u003cp\u003e\u003cb\u003eDevelop drugs with a greater understanding of their physiological effects\u003c\/b\u003e \u003c\/p\u003e\u003cp\u003ePharmaceutical scientists in the fields of pharmacokinetics and pharmacodynamics study how drugs behave in the body and how they reach their site of action to exert their intended pharmacological activities. Drug discovery stands to benefit enormously from the timely application of pharmacokinetics and pharmacodynamics in order to make informed decisions and solve practical problems. \u003c\/p\u003e\u003cp\u003e\u003ci\u003ePutting Pharmacokinetics and Pharmacodynamics to Work in Drug Discovery\u003c\/i\u003e bridges between scientific concepts and practical industrial practice by bringing these principles to bear on every stage of the drug discovery process. Beginning with target identification and moving through each subsequent decision point including high throughput screening, hit-to-lead, lead optimization and candidate selection. The book offers a comprehensive guide to using various analytical tools including modeling and AI\/ML for minimizing attrition, reducing costs, and more. The result is an invaluable tool in developing smarter and more effective drug discovery processes. \u003c\/p\u003e\u003cp\u003e\u003ci\u003ePutting Pharmacokinetics and Pharmacodynamics to Work in Drug Discovery\u003c\/i\u003e readers will also find: \u003c\/p\u003e\u003cul\u003e\n\u003cli\u003eA work designed to make scientific principles accessible to pharmaceutical scientists in diverse areas, not just pharmacokinetists or DMPK scientists\u003c\/li\u003e\n\u003cli\u003eIndustrial examples, both positive and negative, showing pharmacokinetic and pharmacodynamic principles at work\u003c\/li\u003e\n\u003cli\u003eExercises throughout the book to encourage holistic and integrated thinking\u003c\/li\u003e\n\u003c\/ul\u003e \u003cp\u003e\u003ci\u003ePutting Pharmacokinetics and Pharmacodynamics to Work in Drug Discovery\u003c\/i\u003e is ideal for any researchers or professionals involved in drug discovery and development, including medicinal chemists, biopharmaceutics scientists, clinicians, project leaders, and many others.\u003c\/p\u003e","brand":"Wiley","offers":[{"title":"Default Title","offer_id":47989891203301,"sku":"NP9781119650201","price":175.0,"currency_code":"USD","in_stock":false}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/1842\/7735\/files\/9781119650201.jpg?v=1761785812","url":"https:\/\/k12savings.com\/es\/products\/putting-pharmacokinetics-and-pharmacodynamics-to-work-in-drug-discovery-isbn-9781119650201","provider":"K12savings","version":"1.0","type":"link"}