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A comprehensive guide to toxicology in nonclinical drug development /

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A Comprehensive Guide to Toxicology in Nonclinical Drug Development, Third Edition is a valuable reference providing a complete understanding of all aspects of nonclinical toxicology in pharmaceutical research. This updated edition has been expanded and re-developed covering a wide-range of toxicolo...

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Bibliographic Details
Corporate Author: ScienceDirect (Online service)
Other Authors: Faqi, Ali S. (Editor)
Format: eBook
Language:English
Published: London, UK : Academic Press, 2024.
Edition:Third edition.
Subjects:
Drugs > Toxicology.
Drug development.
Médicaments > Toxicologie.
Médicaments > Développement.
Electronic books.
Online Access:Connect to the full text of this electronic book
Table of Contents:
  • Front Cover
  • A COMPREHENSIVE GUIDE TO TOXICOLOGY IN NONCLINICAL DRUG DEVELOPMENT
  • A COMPREHENSIVE GUIDE TO TOXICOLOGY IN NONCLINICAL DRUG DEVELOPMENT
  • Copyright
  • Dedication
  • Contents
  • Contributors
  • Preface
  • I
  • Drug Discovery, Metabolism, and Toxicokinetic
  • 1
  • Introduction to Drug Development
  • References
  • 2
  • Critical Aspects of Integrated Nonclinical Drug Development: Concepts, Strategies, and Potential Pitfalls
  • Introduction
  • Target Identification and Validation
  • Principal Aspects of Preclinical Toxicology Testing
  • Dose Selection for Toxicity Studies with Small Molecules
  • Dose Selection for Toxicity Studies with Biopharmaceuticals
  • Species Selection for Small Molecules
  • Species Selection for Biopharmaceuticals
  • Phase I
  • TGN1412
  • Phase II
  • Introduction of Salt or Change of Salt Form
  • Impurities
  • Phase III
  • Clinical Hold
  • Predictivity of Toxicological Findings for Human Safety
  • Typical Issues and How to Deal with Them
  • Clinical Intolerance and CNS Toxicity
  • Liver Toxicity, Endocrine Disorders, Retinal Toxicity, and Phospholipidosis
  • Cardiotoxicity
  • QT Prolongation
  • Cardiomyopathy
  • The Cardiovascular Safety of Anticancer Therapies
  • Genotoxicity
  • Positive Ames Test-What Next?
  • Positive In Vitro Mammalian Cell Assay-What Next?
  • Carcinogenicity
  • Positive Results in Rodent Carcinogenicity Study-What Next?
  • Examples of Rodent Tumors of Questionable Relevance to Humans
  • Target Organ Concordance Between Test Species and Human
  • Reproductive Toxicity Testing
  • Thalidomide
  • Angiotensin-Converting Enzyme Inhibitors
  • Endothelin Receptor Antagonists
  • Triptanes
  • Postmarketing
  • Drug Withdrawal due to Hepatotoxicity
  • Bromfenac (Duract)
  • Troglitazone (Rezulin)
  • Drug Withdrawal due to Cardiotoxicity
  • Tegaserod (Zelnorm)
  • Sibutramine (Meridia).
  • Concluding Remarks
  • References
  • 3
  • Overview of ADME Science
  • Introduction
  • Specialized Routes of Administration
  • Ocular
  • Transdermal and Topical
  • Inhalation
  • ADME in Drug Discovery
  • Drug Absorption
  • Physicochemical Properties and Permeability in Absorption
  • Drug Transporters in Absorption
  • Membrane-Bound Drug Transporters
  • ATP-Binding Cassette Transport Proteins: P-glycoprotein (P-gp, MDR1, ABCB1)
  • BCRP (MXR, ABCG2)
  • BSEP (SPGP, ABCB11)
  • Solute Carrier Transport Proteins: Organic Anion Transporting Proteins
  • OTC1
  • SLC Transport Proteins
  • Role of Membrane Transporters on ADME Characteristics of Drugs
  • Transporter-Mediated Drug-Drug Interactions: P-glycoprotein
  • Organic Anion (OATs) and Organic Cation Transporters (OCTs)
  • Transporter-Mediated Drug Resistance
  • Methodologies for Evaluating Drug Interactions With Transporters
  • Absorption and Drug Metabolism
  • Metabolism in the GIT and Liver: Stability Testing
  • Stability Testing: Plasma and Microsomal Stability
  • Plasma Stability
  • Microsomal Stability
  • Drug Distribution and Excretion
  • Kinetics of Metabolism in Microsomes, Hepatocyte S9 Fraction, and Hepatocytes
  • Rate of Drug Disappearance in Liver Microsomes or Hepatocytes [85]
  • In Vivo eADME Disposition and Balance Studies
  • Drug Distribution Using Molecular Imaging
  • Drug Metabolism
  • Biotransformation: Drug Metabolite Profile
  • Feces and Other Problematic Milieux
  • Drug Disposition Studies Using MS Without Isotopic Labeling
  • Bioactivation in Drug Metabolism
  • Kinetics of Metabolism in Drug Development
  • Drug-Drug Interactions
  • CYP Inhibition and Phenotyping
  • CYP Induction Studies
  • Summary and Trends
  • Use of Preclinical ADME Data
  • Technologies Impacting ADME in Drug Discovery
  • References
  • Further Reading
  • 4
  • Pharmacokinetics and Toxicokinetics in Drug Development.
  • Introduction
  • Design of Nonclinical PK Experiments
  • Species, Route of Administration, Dose Selection, Frequency, and Experimental Environment
  • Sampling Times and Sample Storage
  • Dosing Formulation and Dose Volume
  • Fed and Fasted States and the Importance of Gender
  • Cassette Dosing
  • Bioanalysis and Software Packages for PK Data Analysis
  • Drug Concentration-Time Relationship
  • Drug Concentration Time Curves: General Considerations
  • Drug Concentration Time Curves Dependency on Sampling and Route of Drug Administration
  • PK Analysis of Drug Concentration Time-Curves: Noncompartmental versus Compartmental PK Analysis
  • Noncompartmental PK Analysis Following a Single Dose
  • Drug Exposure and Bioavailability
  • Terminal Elimination Rate Constant and Half-Life and Mean Residence Time
  • Volume of Distribution
  • Clearance
  • Factors Affecting Clearance and Volume of Distribution
  • PK of Drug Metabolites
  • Noncompartmental PK Analysis Following Multiple Dosing and Intravenous Infusion
  • PK Parameters Derived from Multiple Dosing Studies
  • PK Parameters Derived from Infusion Dose Studies
  • Compartmental PK Analysis
  • One-Compartment Model
  • Multicompartment Models
  • Predicting Human PK Based on Allometric Scaling
  • Allometric Scaling
  • Factors Affecting Allometric Scaling
  • Improving Allometric Scaling: Correction Factors and Different Approaches
  • Prediction of Bioavailability
  • Toxicokinetics in Preclinical Drug Development
  • Traditional Toxicokinetics
  • Differences Between Pharmacokinetics and Toxicokinetics
  • Design of Toxicokinetic Studies
  • Review of Bioanalytical Results for TK Studies
  • Toxicokinetic Analysis
  • Physiologically Based Pharmacokinetic
  • Physiology-Based PK/TK Models Overview
  • PBPK/TK Modeling Guidelines
  • Software Platforms for PBPK Modeling
  • Best Practices for PBPK Models in Drug Evaluation.
  • Role for in Silico and ADME in the Development of PBPK Models
  • Organism Properties in PBPK Models
  • Drug Parameters on PBPK Modeling
  • Constructing a PBPK Model
  • Constructing a PBPK Model for IV and Oral Drug Administration
  • PBPK Model Evaluation
  • PBPK Modeling Using Organ-On-A-Chip' Technology
  • PBPK Model Limitations
  • Conclusions
  • References
  • II
  • Toxicological Studies and IND Application and First-In-Human Clinical Trial and Abuse Liability
  • 5
  • Development of Preclinical Formulations for Toxicology Studies
  • Introduction
  • In Silico, Animal Species, Sampling Volumes, and Sampling Sites
  • In Silico Evaluation
  • Animal Species
  • Circulating Blood Volume
  • Blood Sampling Volume
  • Blood Sampling Sites
  • Dosing Route
  • Oral
  • Intravenous
  • Subcutaneous
  • Intramuscular
  • Intraperitoneal
  • Intraarticular, Intratracheal, and Intraduodenal
  • Dosing Volume
  • Formulation Development
  • Physicochemical Property Characterization
  • Drug-Likeness Rules
  • Solubility
  • Dissolution Rate
  • Ionization Constants and pKa Determination
  • Partition Coefficient
  • Physical and Chemical Stability
  • Biopharmaceutical Classification System
  • Solubility Enhancement
  • pH Adjustment
  • Cosolvents
  • Complexations
  • Surfactants and Micellation
  • Special Dosage Forms
  • Self-Emulsifying Drug Delivery Systems
  • Nanosuspensions/Particles
  • Amorphous Solid Dispersion
  • Decision Tree
  • In Vitro Evaluation of the Performance of a Toxicological Study
  • Case Study
  • Case 1: A Simple Solution Formulation
  • Case 2: A Suspension Formulation With Surfactant
  • Case 3: Nanosuspension by Microfluidization
  • Case 4: An Amorphous Solid Dispersion
  • Concluding Remarks
  • References
  • 6
  • Acute, Subacute, Subchronic, and Chronic General Toxicity Testing for Preclinical Drug Development
  • Introduction.
  • Regulatory Considerations for Conducting Nonclinical Toxicology Studies
  • Selection of Animal Models (Advantages and Disadvantages)
  • Dose Selection and Routes of Administration
  • Study Types Used in the Assessment of General Toxicology
  • Acute/Dose-Range Finding Toxicity Studies
  • Acute/Repeated-Dose Screening Studies
  • Acute Nonclinical Studies for Regulatory Submission
  • Repeated-Dose Toxicity Studies
  • Subacute Toxicity Studies (2-4Weeks)
  • Subchronic Toxicity Studies (13Weeks)
  • Chronic Toxicity Studies (6-12Months)
  • Special Considerations for Biopharmaceutical Safety Evaluations
  • Common Protocol Components of General Toxicity Assessments in GLP Studies
  • Final Thoughts
  • References
  • Further Reading
  • 7
  • Genetic Toxicology Testing
  • Introduction
  • The Concept of Thresholds
  • Genetic Toxicity Testing to Support Clinical Trials
  • Guidelines ICHS2(R1) and ICHM3
  • Option 1
  • Option 2
  • Bacterial Reverse Mutation Assays
  • In Vitro Mammalian Cell Assays
  • In Vitro Chromosome Aberration Test
  • In Vitro Micronucleus Assay
  • Mouse Lymphoma Assay
  • The Sensitivity and Specificity of in Vitro Assays
  • In Vivo Core Tests
  • In Vivo Micronucleus
  • In Vivo Chromosome Aberration Assay
  • Other in Vivo Tests for Genotoxicity
  • DNA Strand-Break Assays: Comet and Alkaline Elution Assays
  • Transgenic Gene Mutation Test
  • Pig-a Gene Mutation Test
  • In Vivo Unscheduled DNA Synthesis Assay
  • Additional Tests Indicating Genotoxicity
  • In Silico Tools
  • In Vitro Comet and in Vitro Alkaline Elution Assays
  • Syrian Hamster Embryo Cell Transformation Assay
  • Green Screen
  • Yeast Deletion Assay
  • DNA Adducts
  • Toxicogenomics
  • Genetox Testing Strategy: Discovery Through Development
  • Early Discovery: Evaluating Chemical Series and Core Structures
  • Lead Optimization
  • Candidate Selection
  • Good Laboratory Practice Studies.