EARLY DRUG DEVELOPMENT -- CONTENTS -- Contributors -- Foreword -- Preface -- PART I INTRODUCTION -- 1 Drug Discovery and Early Drug Development -- 1.1 The Drug Discovery and Development Scene -- 1.1.1 Pharmaceutical Research and Development Challenges -- 1.1.2 Attrition During Discovery and Development -- 1.1.3 Corporate Strategy Perspectives -- 1.2 Drug Discovery -- 1.2.1 Target Identification -- 1.2.2 Hit-to-Lead Identification -- 1.2.3 Lead Optimization Strategies -- 1.3 Pre-FIH Drug Development -- 1.3.1 Introduction -- 1.3.2 Pre-FIH Toxicology -- 1.3.3 Formulation and Drug Delivery -- 1.3.4 Pre-FIH Drug Metabolism and Pharmacokinetics -- 1.4 The FIH Trial -- 1.5 The Regulatory Landscape -- 1.6 Contract Research Organizations -- 1.7 Concluding Remarks on Introductory Perspectives -- References -- PART II LEAD OPTIMIZATION STRATEGIES -- 2 ADME Strategies in Lead Optimization -- 2.1 Introduction -- 2.2 Absorption -- 2.2.1 Permeability -- 2.2.2 Efflux Transport -- 2.3 Distribution -- 2.3.1 Plasma Protein Binding -- 2.3.2 Brain Uptake -- 2.3.3 Tissue Distribution -- 2.4 Metabolism -- 2.4.1 In Vitro Metabolism Studies -- 2.5 Excretion -- 2.6 Pharmacokinetics -- 2.7 Prioritizing ADME Screens -- 2.8 In Silico ADME Screening -- 2.9 The Promise of Metabolomics -- 2.10 Conclusions -- References -- 3 Prediction of Pharmacokinetics and Drug Safety in Humans -- 3.1 Introduction -- 3.2 Prediction of Human Pharmacokinetic Behavior -- 3.2.1 In Vitro Models for Predicting Intestinal Absorption, Intrinsic Hepatic Clearance, and Drug Interactions -- 3.2.2 In Vivo Models for Predicting Pharmacokinetic Behavior -- 3.3 Prediction of Drug Safety -- 3.3.1 In Vitro Approaches for Predicting Drug Safety -- 3.3.2 In Vivo and Ex Vivo Methods for Predicting Drug Safety -- 3.3.3 In Silico Methods for Predicting Drug Safety -- 3.4 Conclusions -- References.

4 Bioanalytical Strategies -- 4.1 Introduction -- 4.1.1 Bioanalysis: The Primary Basis for Pharmacokinetic and Pharmacodynamic Evaluations -- 4.1.2 Regulatory Initiatives in Bioanalysis -- 4.2 Basic Bioanalytical Techniques and Method Development -- 4.2.1 Sample Preparation -- 4.2.2 Component Separation -- 4.2.3 Detection -- 4.2.4 Ligand-Binding Assays -- 4.2.5 Integration of Method Development Components: Example with LC-MS/MS -- 4.3 Bioanalytical Method Validation -- 4.3.1 Introduction to Validation -- 4.3.2 The Primary Metrics: Acceptance Criteria -- 4.3.3 Additional Validation Criteria -- 4.4 Special Issues with Ligand-Binding Assays -- 4.4.1 Characterization -- 4.4.2 Selectivity Issues -- 4.4.3 Matrix Effects -- 4.4.4 Quantification Issues -- 4.5 Partial and Cross-Validations -- 4.6 Application of Validated Methods to Sample Analyses: Some Perspectives -- 4.6.1 Stability -- 4.6.2 Calibration Curves -- 4.6.3 Quality Control Samples -- 4.6.4 Analytical Notes -- 4.6.5 Acceptance Criteria -- 4.6.6 Repeat Analyses of Incurred Samples -- 4.6.7 Sample Stability and Incurred Samples -- 4.6.8 Scientific Versus Production Issues -- 4.6.9 Documentation -- 4.6.10 Resources -- 4.7 Risk-Based Paradigms: Discovery and Development Support -- 4.7.1 Logistics and Discovery -- 4.7.2 Early Involvement of Consultants and CROs -- 4.7.3 Metabolites: Bioanalytical Issues Pre-FIH -- 4.7.4 Racemic Mixtures -- 4.8 The Road to "First in Human" -- 4.8.1 Clinical Collaboration Prior to Initiation of the FIH Trial -- 4.9 International Perspectives -- 4.9.1 European Union -- 4.9.2 Japan -- 4.9.3 India -- 4.10 Conclusions -- References -- PART III BRIDGING FROM DISCOVERY TO DEVELOPMENT -- 5 Chemistry, Manufacturing, and Controls: The Drug Substance and Formulated Drug Product -- 5.1 Introduction -- 5.2 Pre-NCE Activities and CMC Development.

5.2.1 Rationale for CMC Involvement in Discovery -- 5.2.2 Pharmaceutical Properties -- 5.2.3 CMC Interactions with Discovery at NCE Selection -- 5.2.4 Biopharmaceuticals -- 5.3 CMC Considerations at the NCE Stage -- 5.3.1 Solid-State Compounds -- 5.3.2 Selection of Development Form (Crystalline State) -- 5.3.3 Characterization of Drug Substance (Preformulation) -- 5.4 NCE-to-GLP Transition (Bridging from Discovery to Pre-FIH Development) -- 5.4.1 Drug Synthesis and Formulation for Toxicity Studies: Meeting the Delivery Objectives -- 5.4.2 Bridging to Formulations for FIH Studies -- 5.5 CMCs to Meet Clinical Trial Material Requirements -- 5.5.1 Drug Substance Comparability with Material Used in Pre-FIH GLP Studies -- 5.5.2 Good Manufacturing Practices -- 5.5.3 Analytical Development for Assay of Drug Substance and Drug Product -- 5.5.4 Placebos and Blinding -- 5.6 CMC Strategic Considerations -- 5.6.1 Interactions Across Disciplines -- 5.6.2 Outsourcing (and Insourcing) CMC Work -- 5.7 Case Studies -- 5.7.1 Indinavir -- 5.7.2 Doxorubicin Peptide Conjugate -- 5.8 Evolution of Drug Development: Implications for CMCs in the Future -- Resources -- References -- 6 Nonclinical Safety Pharmacology Studies Recommended for Support of First-in-Human Clinical Trials -- 6.1 Introduction and Overview -- 6.2 Timing of Safety Pharmacology Studies -- 6.3 CNS Safety Pharmacology -- 6.4 Cardiovascular Safety Pharmacology -- 6.4.1 Study Designs -- 6.4.2 Additional Information on QT-Interval Prolongation or Delayed Ventricular Repolarization -- 6.5 Respiratory System Safety Pharmacology -- 6.6 Renal/Urinary Safety Pharmacology -- 6.7 Gastrointestinal System Safety Pharmacology -- 6.8 Autonomic Nervous System Safety Pharmacology -- 6.9 Other Systems -- 6.10 Discussion and Conclusions -- References -- PART IV PRE-IND DRUG DEVELOPMENT.

7 Toxicology Program to Support Initiation of a Clinical Phase I Program for a New Medicine -- 7.1 Introduction -- 7.2 Toxicology Support of Discovery -- 7.3 Goals of the Pre-FIH Toxicology Program -- 7.4 Importance of a Clinical Review of the Nonclinical Pharmacology Data -- 7.5 Take the Time to Plan Appropriately -- 7.6 The Active Pharmaceutical Ingredient -- 7.6.1 Availability Issues -- 7.6.2 Impurity Considerations -- 7.6.3 Inactive Ingredients -- 7.7 Timely Conduct of In Vitro Assays -- 7.7.1 Comparative In Vitro Metabolism -- 7.7.2 Genetic Toxicology -- 7.8 Development of Validated Bioanalytical and Analytical Assays -- 7.8.1 Validated Bioanalytical Assay for Determining Plasma Concentrations of the NCE -- 7.8.2 Validated Analytical Assays for Dosing Solutions or Suspensions -- 7.8.3 Validated Assays for Dosing Solution Stability -- 7.9 Planning for the Conduct of Toxicity Studies -- 7.9.1 Timing of the IND/CTA -- 7.9.2 The Danger of Shortcuts -- 7.9.3 Pilot In Vivo Studies for Dose Selection and Bleeding Time Determinations -- 7.10 GLP Toxicology Program -- 7.10.1 Toxicology Requirements for Initiating an FIH Trial -- 7.10.2 Toxicology Protocols -- 7.10.3 Study Monitoring -- 7.10.4 Microscopic Examination of Tissues -- 7.10.5 Considerations of the NOAEL and MTD in Protocol Design -- 7.11 Pre-IND Meeting -- 7.12 Conclusions -- References -- 8 Toxicokinetics in Support of Drug Development -- 8.1 Introduction -- 8.2 Historical Perspectives -- 8.3 Regulatory Considerations -- 8.4 Factors to Consider in the Design of Toxicokinetic Studies -- 8.4.1 Drug Supply Requirements -- 8.4.2 Species Selection -- 8.4.3 API Properties: Salt/Crystal Form, Particle Size, and Impurities -- 8.4.4 Dose-Related Exposure -- 8.4.5 Changes in Pharmacokinetics Following Multiple Dosing -- 8.4.6 Selection of Dosing Vehicles -- 8.4.7 Bioanalytical Method.

8.4.8 Evaluation of Metabolites -- 8.4.9 Evaluation of Enantiomers -- 8.4.10 Matrix Considerations -- 8.4.11 Number of Animals -- 8.4.12 Gender -- 8.4.13 Dose Selection -- 8.4.14 Dose Volume -- 8.4.15 Blood Sampling Variables -- 8.4.16 Sampling Times -- 8.4.17 Considerations with Biopharmaceutics -- 8.4.18 Practical Considerations in Planning a Toxicokinetic Program -- 8.5 Toxicokinetic Parameter Estimates and Calculations -- 8.5.1 Data Analysis (Noncompartmental Versus Compartmental) -- 8.5.2 Noncompartmental Kinetic Parameters -- 8.5.3 Statistics and Outliers -- 8.5.4 Physiologically Based Toxicokinetic Modeling -- 8.6 Interpretation of Toxicokinetic Data -- 8.6.1 Review of In-life Results -- 8.6.2 Protocol Deviations -- 8.6.3 Confirmation of Exposure and Evaluation of Dose Proportionality -- 8.6.4 Exposure after Single and Multiple Dosing: Accumulation Perspectives -- 8.6.5 Gender Effects -- 8.6.6 Relationship to Toxicology Findings -- 8.6.7 Midstudy Changes in Dosing Duration or Dose Level -- 8.7 Role of Toxicokinetics in Different Types of Toxicity Studies -- 8.7.1 Acute Studies -- 8.7.2 Dose-Range-Finding and Tolerability Studies -- 8.7.3 Subchronic Studies (Two Weeks to Three Months) -- 8.7.4 Chronic Studies (Six to 12 Months) -- 8.7.5 Safety Pharmacology and Specialty Studies -- 8.7.6 Genetic Toxicology -- 8.7.7 Reproductive Toxicology -- 8.7.8 Carcinogenicity Studies -- 8.7.9 Bridging Toxicity Studies -- 8.8 Role of Toxicokinetics in Integrated Safety Assessment -- 8.8.1 Safety Margins: Role in Setting Clinical Doses for FIH Studies -- 8.8.2 Role of Protein Binding and Blood Partitioning -- 8.8.3 Toxicokinetics: Caution about Safety Margins -- 8.8.4 Safety Margins for Different Toxicity Profiles -- 8.9 Conclusions -- References -- 9 Good Laboratory Practice -- 9.1 Introduction -- 9.2 Hazard and Risk -- 9.3 U.S. GLP Regulations.

9.3.1 Subpart A: General Provisions.