Drug Discovery and Development

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
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