دانلود کتاب Drug Discovery and Development

فهرست مطالب :

Front-Matter_2013_Drug-Discovery-and-Development Drug Discovery and Development Copyright_2013_Drug-Discovery-and-Development Copyright page Foreword_2013_Drug-Discovery-and-Development Foreword Preface-to-2nd-Edition_2013_Drug-Discovery-and-Development Preface to 2nd Edition Preface-to-1st-edition_2013_Drug-Discovery-and-Development Preface to 1st edition Contributors_2013_Drug-Discovery-and-Development Contributors Chapter-1---The-development-of-the-pharmaceutic_2013_Drug-Discovery-and-Deve 1 The development of the pharmaceutical industry Antecedents and origins Therapeutics in the 19th century An industry begins to emerge Developments in biomedicine Developments in chemistry The apothecaries’ trade The industry enters the 20th century Chemistry-driven drug discovery Synthetic chemistry Natural product chemistry Target-directed drug discovery The sulfonamide story Hitchings and Elion and the antimetabolite principle James Black and receptor-targeted drugs Accidental clinical discoveries The regulatory process Concluding remarks References Chapter-2---The-nature-of-disease-and-the-purpo_2013_Drug-Discovery-and-Deve 2 The nature of disease and the purpose of therapy Introduction Concepts of disease What is health? What is disease? Deviation from normality does not define disease Phenomenology and aetiology are important factors – the naturalistic view Harm and disvalue – the normative view The aims of therapeutics Components of disvalue Therapeutic intervention is not restricted to treatment or prevention of disease Conclusions Function and dysfunction: the biological perspective Levels of biological organization Therapeutic targets The relationship between drug targets and therapeutic targets Therapeutic interventions Measuring therapeutic outcome Effect, efficacy, effectiveness and benefit Pharmacoepidemiology and pharmacoeconomics Summary References Chapter-3---Therapeutic-modalities_2013_Drug-Discovery-and-Development 3 Therapeutic modalities Introduction Conventional therapeutic drugs Biopharmaceuticals Gene therapy Cell-based therapies Tissue and organ transplantation Summary References Chapter-4---The-drug-discovery-process--General-prin_2013_Drug-Discovery-and 4 The drug discovery process: Introduction Some case histories Paclitaxel (Taxol) Flecainide (Tambocor) Omeprazole (Losec) Imatinib (Gleevec/Glivec) Trastuzumab (Herceptin) Comments and conclusions The stages of drug discovery Trends in drug discovery Project planning Research in the pharmaceutical industry References Chapter-5---Choosing-the-project_2013_Drug-Discovery-and-Development 5 Choosing the project Introduction Making the decision Strategic issues Unmet medical need Market considerations Company strategy and franchise Legislation, government policy, reimbursement and pricing Scientific and technical issues The scientific and technological basis Competition Development and regulatory hurdles The patent situation Operational issues A final word Chapter-6---Choosing-the-target_2013_Drug-Discovery-and-Development 6 Choosing the target Introduction: the scope for new drug targets How many drug targets are there? The nature of existing drug targets Conventional strategies for finding new drug targets New strategies for identifying drug targets Trawling the genome Disease genes Disease-modifying genes Gene expression profiling Gene knockout screening ’Druggable’ genes Target validation Pharmacological approaches Genetic approaches Antisense oligonucleotides RNA interference (RNAi) Transgenic animals Summary and conclusions References Chapter-7---The-role-of-information--bioinformat_2013_Drug-Discovery-and-Dev 7 The role of information, bioinformatics and genomics The pharmaceutical industry as an information industry Innovation depends on information from multiple sources Bioinformatics Bioinformatics as data mining and inference General principles for data mining Pattern discovery Predictive analysis Association analysis Genomics The genome and its offspring ‘-omes’ A few genome details Genome variability and individual differences The epigenome The transcriptome In defence of the genome Genomic information in drug discovery and development Understanding human disease intrinsic mechanisms Understanding the biology of infectious agents Identifying potential drug targets Validating drug targets Assay development for selected drug targets Phase 0 clinical studies – understanding from compounds in low concentration Phase I clinical studies – pharmacokinetics and safety Phase II and III clinical studies – efficacy and safety Genomic information and drug regulatory authorities Critical Path Initiative and the EMEA’s equivalent programme Voluntary exploratory data submissions and guidance documents Conclusion References Chapter-8---High-throughput-screening_2013_Drug-Discovery-and-Development 8 High-throughput screening Introduction: a historical and future perspective Lead discovery and high-throughput screening Assay development and validation Biochemical and cell-based assays Assay readout and detection Ligand binding assays Fluorescence technologies Fluorescence intensity Fluorescence resonance energy transfer (FRET) Time resolved fluorescence (TRF) Fluorescence polarization (FP) Fluorescence correlation methods AlphaScreen™ Technology Cell-based assays Readouts for cell-based assays Fluorometric assays Reporter gene assays Yeast complementation assay High throughput electrophysiology assays Label free detection platforms High content screening Biophysical methods in high-throughput screening Assay formats – miniaturization Robotics in HTS Data analysis and management Screening libraries and compound logistics Compound logistics Profiling References Chapter-9---The-role-of-medicinal-chemistry-in-the_2013_Drug-Discovery-and-D 9 The role of medicinal chemistry in the drug discovery process Introduction Target selection and validation Lead identification/generation Lead optimization Addressing attrition Summary References Chapter-10---Metabolism-and-pharmacokinetic-optimiza_2013_Drug-Discovery-and 10 Metabolism and pharmacokinetic optimization strategies in drug discovery Introduction Optimization of DMPK properties Absorption and oral bioavailability Introduction Tactics Cautions Avoidance of PK based drug–drug interactions Introduction Tactics Competitive (reversible) CYP inhibition Mechanism-based/time-dependent CYP inhibition Uptake and efflux transporter inhibition Determination of clearance mechanism and CYP phenotyping CYP induction mediated risk for DDI Prediction of DDI risk Cautions Central nervous system uptake Introduction Tactics Cautions Clearance optimization Introduction Optimization of metabolic clearance Introduction Tactics Cautions Optimization of renal clearance Introduction Tactics Cautions Optimization of biliary clearance Introduction Tactics Cautions Role of metabolite identification studies in optimization Introduction Active metabolites Introduction Tactics Cautions Minimizing risk for reactive metabolites during drug discovery Introduction Tactics Caution Human PK and dose prediction Prediction of absorption rate and oral bioavailability Prediction of clearance Prediction of volume of distribution Prediction of plasma concentration time profile Prediction of human efficacious dose Summary Acknowledgments References Chapter-11---Pharmacology--Its-role-in-drug-d_2013_Drug-Discovery-and-Develo 11 Pharmacology: Introduction Screening for selectivity Interpretation of binding assays Pharmacological profiling In vitro profiling Measurements on isolated tissues In vivo profiling Species differences Animal models of disease Types of animal model Genetic models The choice of model Validity criteria Some examples Epilepsy models Psychiatric disorders Stroke Good laboratory practice (GLP) compliance in pharmacological studies References Chapter-12---Biopharmaceuticals_2013_Drug-Discovery-and-Development 12 Biopharmaceuticals Introduction Recombinant DNA technology: the engine driving biotechnology The early days of protein therapeutics Currently available classes of biopharmaceuticals Growth factors and cytokines Hormones Coagulation factors Antithrombotic factors Therapeutic antibodies Monoclonal antibodies Antibody selection by phage display Uses of antibodies as therapeutic agents Cancer immunotherapy Antibody use in transplantation and immunomodulation Catalytic antibodies Therapeutic enzymes Vaccines Gene therapy Introduction of genetic material into cells Delivery of nucleic acids Strategies for nucleic acid-mediated intervention RNA interference – gene silencing by RNAi Comparing the discovery processes for biopharmaceuticals and small molecule therapeutics Manufacture of biopharmaceuticals Expression systems Engineering proteins Site-directed mutagenesis Fused or truncated proteins Protein production Pharmacokinetic, toxicological and drug-delivery issues with proteins and peptides Absorption of protein/peptide therapeutics Mucosal delivery Parenteral delivery Elimination of protein/peptide therapeutics Summary References Chapter-13---Scaffolds--Small-globular-proteins-as_2013_Drug-Discovery-and-D 13 Scaffolds: Introduction Scaffolds Kunitz type domains Tenth type III domain of fibronectin (Adnectins) A-domains (Avimers) SH3 domain of Fyn kinase (Fynomers) Affibodies: Z-domain of staphylococcal protein A Ankyrin repeat proteins (DARPins) Lipocalins Single domain antibodies Other domains Concluding remarks References Chapter-14---Drug-development--Introductio_2013_Drug-Discovery-and-Developme 14 Drug development: Introduction The nature of drug development Components of drug development The interface between discovery and development Decision points The need for improvement References Chapter-15---Assessing-drug-safety_2013_Drug-Discovery-and-Development 15 Assessing drug safety Introduction Types of adverse drug effect Safety pharmacology Tests for QT interval prolongation Exploratory (dose range-finding) toxicology studies Genotoxicity Selection and interpretation of tests Chronic toxicology studies Experimental design Evaluation of toxic effects Biopharmaceuticals Special tests Carcinogenicity testing Reproductive/developmental toxicology studies Other studies Toxicokinetics Toxicity measures Variability in responses Conclusions and future trends References Chapter-16---Pharmaceutical-development_2013_Drug-Discovery-and-Development 16 Pharmaceutical development Introduction Preformulation studies Solubility and dissolution rate Stability Particle size and morphology Routes of administration and dosage forms Formulation Principles of drug delivery systems Polymers and surfactants Micelles Liposomes Nanontechnology more then nanoparticles Modified-release drug formulations Delivery and formulation of biopharmaceuticals Drug delivery to the central nervous system Summary References Chapter-17---Clinical-development--present-an_2013_Drug-Discovery-and-Develo 17 Clinical development: Introduction Clinical development phases Phase I – Clinical pharmacology First in man, single ascending dose, pharmacokinetics and safety Objectives Subjects Design Outcome measures Multiple ascending repeat-dose studies Design Outcome measures Pharmacodynamic studies Drug–drug interaction studies Absolute bioavailability and bioequivalence of new formulations Absorption distribution metabolism excretion (ADME) in man (radiolabelled studies) Other safety pharmacology studies Special populations Phase IIa – Exploratory efficacy Objectives Design consideration for first in class compounds – large pharma vs small pharma Design Patients to be studied Outcome measures Phase IIb to III dose range finding and confirmatory efficacy studies Objectives Design Patients and study setting Outcome measures Phase IIIb and IV studies Bridging studies Patient recruitment in efficacy studies Clinical trials in children Regulatory and ethical environment Ethical procedures Clinical trial operations and quality assurance Issues of confidentiality and disclosure Seamless drug development with adaptive clinical trial design: the future of clinical development? Conclusions References Chapter-18---Clinical-imaging-in-drug-develo_2013_Drug-Discovery-and-Develop 18 Clinical imaging in drug development Introduction Imaging methods Positron emission tomography (PET) Magnetic resonance imaging (MRI) Functional magnetic resonance imaging (fMRI) Human target validation Biodistribution Target interaction Pharmacodynamics Patient stratification and personalized medicine Towards personalized medicine Imaging as a surrogate marker Imaging in the real world – challenges to implementation Summary Acknowledgments References Chapter-19---Intellectual-property-in-drug-discov_2013_Drug-Discovery-and-De 19 Intellectual property in drug discovery and development What is a patent? The patent specification Bibliographic details Description Claims What can be patented? Pharmaceutical inventions Requirements for patentability Novelty Novelty in the USA Inventive step (non-obviousness) Industrial applicability (utility) Patent issues in drug discovery The state of the art Patent documents as state of the art Evaluation by the scientist Evaluation by the patent professional Sources of information Results of the evaluation – NCEs Patenting of research tools Obtaining patent protection for a development compound Filing a patent application When to file Where to file The foreign filing decision Abandonment Refiling Home-country patenting Foreign filing Procedures on foreign filing National filings Regional patent offices Patent cooperation treaty (PCT) Selection of countries Maintenance of patents Extension of patent term Enforcement of patent rights Other forms of intellectual property Further reading Useful websites Patent offices Professional organizations Lists of links Chapter-20---Regulatory-affairs_2013_Drug-Discovery-and-Development 20 Regulatory affairs Introduction Brief history of pharmaceutical regulation International harmonization Roles and responsibilities of regulatory authority and company The role of the regulatory affairs department The drug development process Quality assessment (chemistry and pharmaceutical development) Safety assessment (pharmacology and toxicology) Primary pharmacology General pharmacology Pharmacokinetics: absorption, distribution, metabolism and excretion (ADME) Toxicology Single and repeated-dose studies Genotoxicity Carcinogenicity Reproductive and developmental toxicity Local tolerance and other toxicity studies Efficacy assessment (studies in man) Human pharmacology Therapeutic exploratory studies Studies in special populations: elderly, children, ethnic differences Clinical trials in children Ethnic differences Therapeutic confirmatory studies Clinical safety profile Regulatory aspects of novel types of therapy Biopharmaceuticals Quality considerations Safety considerations Efficacy considerations Regulatory procedural considerations Personalized therapies Orphan drugs Environmental considerations Regulatory procedures Clinical trials Europe USA Japan Application for marketing authorization Europe USA Japan The common technical document Administrative rules Patent protection and data exclusivity Supplementary protection certificate Data exclusivity Pricing of pharmaceutical products – ‘the fourth hurdle’ References Website references List of abbreviations Chapter-21---The-role-of-pharmaceutical-mark_2013_Drug-Discovery-and-Develop 21 The role of pharmaceutical marketing Introduction History of pharmaceutical marketing Product life cycle Product development phase Introduction phase Growth phase Maturity phase Decline phase Pharmaceutical product life cycle (Figure 21.3) Traditional Pharmaceutical marketing Clinical studies Identifying the market The product Features, attributes, benefits, limitations (FABL) Assessing the competition e-Marketing CME Key opinion leaders Pricing Freedom of pricing Regulated pricing Health technology assessment (HTA) New product launch Registration Manufacturing and distribution Resource allocation Launch meeting Media launch Target audience The influence of innovators and early adopters on group prescribing Patients driving launch success The first 6 months Decline in prescriber decision-making power Implementing the market plan Changing environment – changing marketing The key stakeholder Values of the stakeholders Innovation R&D present and future Products of the future The future of marketing The new way of marketing References Chapter-22---Drug-discovery-and-development--fac_2013_Drug-Discovery-and-Dev 22 Drug discovery and development: Spending How much does it cost to develop a drug? Sales revenues Profitability Pattern of sales Blockbuster drugs Timelines Pipelines and attrition rates Biotechnology-derived medicines Recent introductions Predicting the future? References No-title-available_2013_Drug-Discovery-and-Development Index A B C D E F G H I J K L M N O P Q R S T U V W X Y Z