How Drugs Are Developed: 3rd Edition

Table of Contents

INTRODUCTION

CHAPTER 1 DRUG TARGETS AND TARGET HUNTING

• 1.1 Target hunting
  • 1.1.1 Proteins as drug targets
  • 1.1.2 Enzymes and the significance of protein folding
  • 1.1.3 Protein synthesis
  • 1.1.4 Further processing of proteins
• 1.2 The range of drug targets
  • 1.2.1 Bioinformatics
  • 1.2.2 Systems biology
  • 1.2.3 Metabonomics
• 1.3 The range of drugs
  • 1.3.1 Enzyme inhibition
  • 1.3.2 7-transmembrane receptors (7TMs)

CHAPTER 2 LEAD GENERATION

• 2.1 Introduction
• 2.2 Small molecule lead generation
  • 2.2.1 Units
  • 2.2.2 Lead generation strategies
  • 2.2.3 Lipinski' s rule of 5
  • . . . molecular size
  • . . . fatty/aqueous considerations
  • . . . hydrogen bonding
  • 2.2.4 Fragment-based lead generation
  • 2.2.5 Chemi-informatic filters
• 2.3 Practical lead generation
  • 2.3.1 High throughput screening (HTS)
  • 2.3.2 Receptor binding assays
• 2.4 Combinatorial chemistry
• 2.5 Parallel synthesis
• 2.6 Structure/activity relationships (SARs)
• 2.7 SAR, quantified structure/activity relationships and CADD
• 2.8 Secondary screening
• 2.9 Biotechnology and lead generation
  • 2.9.1 Mimicry of the natural ligand
  • 2.9.2 Recombinant technology
  • 2.9.3 Recombinant Factor VIII
  • 2.9.4 Recombinant erythropoietin
  • 2.9.5 Monoclonal antibodies
  • 2.9.6 Monoclonal antibodies and immunogenicity
  • 2.9.7 Mechanism of action
  • 2.9.8 Advantages and disadvantages of biological products versus small molecules

CHAPTER 3 LEAD OPTIMISATION

• 3.1 Early safety screening
  • 3.1.1 Genetic toxicity
  • 3.1.2 e-screens for genetic toxicity
  • 3.1.3 General toxicity screening
  • 3.1.4 Screening for genetic toxicity - the Ames test
  • 3.1.5 Mouse lymphoma assay (MLA)
  • 3.1.6 Clastogenicity
• 3.2 HTS bioavailability and pharmacokinetics
  • 3.2.1 Models of absorption
  • 3.2.2 Metabolism
  • 3.2.3 Optimisation of biologicals
• 3.3 Summary

CHAPTER 4 PREPARING FOR DEVELOPMENT

• 4.1 Patent filing
  • 4.1.1 Competitor surveillance
• 4.2 Optimisation for potency
• 4.3 In vivo activity
• 4.4 Therapeutic ratio and a consistent drug delivery
• 4.5 Efficacy, toxicity and dose consistency - the basis of preclinical research
• 4.6 In search of dosing consistency
  • 4.6.1 The significance of low bioavailability
  • 4.6.2 Optimisation of bioavailability
  • . . . aqueous solubility
  • . . . particle crystallinity and size
  • . . . polymorphism
  • 4.6.3 Stability
  • 4.6.4 Salt formation
  • 4.6.5 Solution stability
• 4.7 Drug disposition and bioavailability
  • 4.7.1 Absorption and distribution
    • 4.7.1.1 Metabolism and excretion
    • . . . a metabolite may be more active than the parent
    • . . . enzyme inhibition, induction and polymorphism
    • . . . Phase-1 and Phase-2 metabolism
• 4.8 Pharmacokinetics (primer)
  • 4.8.1 Cassette dosing
  • 4.8.2 Absolute bioavailability
• 4.9 Drug safety
  • 4.9.1 Toxicogenomics
  • 4.9.2 Safety pharmacology
    • 4.9.2.1 Receptor and enzyme screening
    • 4.9.2.2 Cardiovascular toxicity
    • . . . HERG assay
    • . . . in vivo cardiovascular screening
    • 4.9.2.3 Respiratory system
    • 4.9.2.4 Central nervous system (CNS) screening
• 4.10 Good laboratory practice
• 4.11 Summary statements
• 4.12 Project progression criteria
  • 4.12.1 Target proposal
  • 4.12.2 Nomination of a lead
  • 4.12.3 Nomination of a development candidate
    • 4.12.3.1 Biology
    • 4.12.3.2 Patent
    • 4.12.3.3 Chemistry
    • 4.12.3.4 Pharmaceutics
    • 4.12.3.5 Drug disposition
    • 4.12.3.6 Safety
• 4.13 Preparing a biological candidate for development
  • 4.13.1 API preparation
  • 4.13.2 Biological drug quality and cell banking
  • 4.13.3 Bioreactors
  • 4.13.4 Clinical formulation
  • 4.13.5 Biologic progression criteria
• 4.14 The case for development

CHAPTER 5 PRECLINICAL RESEARCH

• 5.1 Introduction
• 5.2 Drug substance supplies (kilogram-scale chemistry and bioprocessors)
  • 5.2.1 Patents
  • 5.2.2 Environment
  • 5.2.3 Health and safety
  • 5.2.4 Raw material sourcing and pricing
  • 5.2.5 Scalability
  • 5.2.6 Optimisation
  • 5.2.7 Liaison with the pharmaceutical department
• 5.3 Good manufacturing practice (GMP)
• 5.4 Synthetic route optimisation
  • 5.4.1 The early synthetic route for fluoxetine
  • 5.4.2 The final (or manufacturing) route for fluoxetine
  • 5.4.3 Analytical sciences and impurities
  • 5.4.3.1 The importance of finalising the route to drug substance early
  • 5.4.4 Manufacture of biological drugs
  • 5.4.5 API specification
  • 5.4.6 Stability
• 5.5 Investigational medicinal product (IMP) development
  • 5.5.1 The oral dosage form
  • . . . direct compression
  • . . . dry granulation
  • . . . wet granulation
  • . . . tablet coating
  • 5.5.2 Intravenous dosage form
  • 5.5.3 Specifications and stability
• 5.6 Non-clinical safety assessment
  • 5.6.1 General toxicology
  • 5.6.2 The regulatory requirements for FIM
  • . . . toxicokinetics
  • . . . safety study outcomes
  • . . . late-stage safety development programme
  • 5.6.3 Reproductive toxicology
  • . . . embryo-foetal development (EFD) testing (segment II)
  • . . . fertility testing (segment I)
  • . . . peri and postnatal toxicity trials (segment III)
  • 5.6.4 Special considerations for biologicals
  • . . . pharmacokinetics
  • . . . immunotoxicity
  • 5.6.5 Genetic toxicity and carcinogenicity
  • . . . the Ames test for regulatory submission
  • . . . chromosomal aberration test
  • . . . in vivo clastogenicity testing
  • . . . carcinogenicity testing
  • 5.6.6 High-risk medicinal products
• 5.7 Drug disposition
  • 5.7.1 Pharmacokinetics
  • . . . bioavailability
  • . . . distribution
  • . . . elimination and clearance
  • . . . therapeutic window
  • . . . PK/PD modelling
  • 5.7.2 ADME
  • . . . multi-resistance drug protein (MDR)
  • . . . blood-brain barrier
  • . . . plasma protein binding
  • . . . distribution
  • . . . mass balance study
  • . . . tissue distribution studies
  • . . . bile elimination studies
  • . . . drug disposition as the linchpin of drug development

CHAPTER 6 TRANSLATIONAL RESEARCH

• 6.1 Introduction
  • 6.1.1 Proof of concept studies
  • 6.1.2 Biomarkers
  • 6.1.3 Translational research in oncology
  • 6.1.4 Translational research and safety
    • 6.1.4.1 The heart and the liver
    • 6.1.4.2 Translational research and metabolism

CHAPTER 7 PROJECT MANAGEMENT

• 7.1 Introduction
  • 7.1.1 The project team
  • 7.1.2 The kick-off meeting
  • 7.1.3 The project plan
  • 7.1.4 Maintaining progress
• 7.2 The project team as the company experts
• 7.3 Project teams as mediators of innovation
• 7.4 Project teams and outsourcing
• 7.5 Project managers

CHAPTER 8 REGULATORY SUBMISSIONS

• 8.1 Introduction - the regulatory bodies
  • 8.1.1 The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
  • 8.1.2 The major regulatory bodies of the world
  • . . . European Agency for the Evaluation of Medicinal Products (EMEA)
  • . . . US Food and Drug Administration (FDA)
  • . . . the Japanese Ministry for Health, Labour and Welfare (MHLW)
• 8.2 Regulatory submissions
  • 8.2.1 Application to conduct a clinical trial
  • . . . clinical trial application in the US (IND)
  • . . . and Europe (CTA)
  • 8.2.2 Changes to the European system for application to conduct clinical trials
  • 8.2.4 The investigator' s brochure (IB)
• 8.3 Regulatory strategy
  • 8.3.1 Quality
  • 8.3.2 Preclinical safety
  • 8.3.3 Linking it all together
• 8.4 Application to market a new drug
  • 8.4.1 The European licensing system
  • . . . the centralised procedure
  • . . . the mutual recognition procedure
  • . . . national submissions
  • 8.4.2 The common technical document
  • 8.4.3 Electronic CTD submissions (e-CTD)
  • 8.4.4 Marketing applications in the US
  • 8.4.5 Special examples of drug approval processes
  • . . . accelerated approval
  • . . . orphan drug status

CHAPTER 9 CLINICAL EVALUATION

• 9.1 Introduction
• 9.2 Definitions
• 9.3 Clinical trial regulation
  • 9.3.1 Ethics committee approval
  • 9.3.2 The clinical team
  • 9.3.3 Required documentation
• 9.4 The categories of clinical trials
  • 9.4.1 Characteristics of Phase I trials
  • . . . ADME parameters
  • . . . blood biochemistry
  • . . . dose escalation, single and multiple dose studies
  • 9.4.2 Clinical pharmacokinetics
  • . . . Phase I PK monitoring
  • . . . human microdosing
  • . . . PK trials for specific purposes
  • . . . the elderly
  • . . . paediatrics
  • . . . interaction with food
  • . . . bioequivalence trials
  • . . . specific population groups
• 9.5 Phase II studies
• 9.6 Phase II/III Go/NoGo
• . . . reasons for a project NoGo before Phase III
• 9.7 Phase III
  • 9.7.1 Characteristics of Phase III trials
  • 9.7.2 Example - rimonabant in Phase III
• 9.8 Pharmacoeconomics
  • 9.8.1 Trials with pharmacoeconomic endpoints
  • 9.8.2 Assessing technological advances
  • 9.8.3 The basis of NICE analyses
• 9.9 Concluding summary

CHAPTER 10 POSTMARKETING SURVEILLANCE (PMS)

• 10.1 Introduction
• 10.2 The need for PMS
• 10.3 Pharmacovigilance
  • 10.3.1 Drug safety
  • 10.3.2 Risk/benefit assessment
  • . . . evaluating risk
  • . . . evaluating benefit
• 10.4 The mechanics of pharmacovigilance
  • 10.4.1 PSURs
  • 10.4.2 Expedited reports
• 10.5 Risk management
• 10.6 Pharmacovigilance specification
  • 10.6.1 Developmental data
  • 10.6.2 Class effects
  • 10.6.3 Drug interactions
  • 10.6.4 Less obvious contingencies
• 10.7 The risk management plan
  • 10.7.1 Risk management in Europe
  • 10.7.2 The withdrawal of Vioxx
  • 10.7.3 Rimonabant

LIST OF TABLES

• Table 2.1 Units of molarity in decreasing concentration
• Table 2.2 Example of structure/activity table for hypothetical molecule
• Table 5.1 Example of specification for final API

LIST OF FIGURES

• Figure 1.1 Amino acid structure illustrating amino group and carboxylic acid by which peptide bonds and chains of amino acids are formed
• Figure 1.2 A sequence of amino acids linked through peptide bonds to form a peptide (a mini protein)
• Figure 1.3 The structure of myoglobin, a muscle protein rich in secondary folding characterised as a-helices
• Figure 1.4 Tertiary folding of protein chains in an imaginary enzyme
• Figure 1.5 The main steps of protein synthesis
• Figure 1.6 The essential elements of DNA
• Figure 1.7 Base pairing, the triplet code and protein synthesis
• Figure 1.8 Simplified illustration of the consequences of insulin receptor activation
• Figure 1.9 Principles of Serenex' s chemical genomics capability
• Figure 1.10 Illustration of cholesterol synthesis and control by HMGCoAR
• Figure 1.11 Nervous control of heart rate
• Figure 1.12 The generic cell and its drug targets
• Figure 2.1 Structural similarity between serotonin and sumatriptan
• Figure 2.2 The structures of cholesterol and lovastatin
• Figure 2.3 Computer model of ligand - protein interaction
• Figure 2.4 Charge change on amino acid with rising pH
• Figure 2.5 Illustration of hydrogen bond formation between water molecules
• Figure 2.6 Schematic of a sample receptor binding assay
• Figure 2.7 Illustration of 96-well microtitre plates, variants of which are used for combinatorial synthesis
• Figure 2.8 Combinatorial synthesis of hypothetical peptides
• Figure 2.9 The basic components of solid-phase combinatorial chemistry
• Figure 2.10 Representation of first stages of a solid-phase combinatorial synthetic plate
• Figure 2.11 Simplified network of intracellular enzyme activation
• Figure 2.12 Hypothetical proteins and their active sites
• Figure 2.13 Illustration of generation and joining of cohesive ends of two sequences to produce a new sequence
• Figure 2.14 Structure of an antibody
• Figure 2.15 Mechanism of action of Herceptin
• Figure 3.1 Safety studies likely to be included in lead generation and optimisation
• Figure 3.2 Possible outcomes from the Ames test
• Figure 3.3 Illustration of the barriers to drug absorption and distribution
• Figure 3.4 Intestinal cells grown to confluence to form a barrier between upper and lower chambers of culture wells
• Figure 3.5 Illustrative copy of various published datasets showing the correlation between human absorption and Papp for a series of known drugs
• Figure 4.1 The Eternal Triangle ................................................... efficacy, safety and dose delivery
• Figure 4.2 Schematic of the metabolism of a hypothetical drug
• Figure 4.3 Illustration of the entero-hepatic shunt and drug recycling
• Figure 4.4 Pharmacokinetic trace of hypothetical orally administered drug
• Figure 4.5 Pharmacokinetic trace of orally administered drug set against its in vitro potency
• Figure 4.6 Comparative pharmacokinetic curves for three development candidates
• Figure 4.7 Pharmacokinetic traces obtained for a drug following oral and iv dosing
• Figure 4.8 Relationship between Kr channel inhibition and terfenadine concentration
• Figure 5.1 The CDP as a stimulus and guide for preclinical development
• Figure 5.2 Simplified project plan around the time of candidate selection through to first in man (FIM) trials
• Figure 5.3 Early synthetic route for fluoxetine (Prozac)
• Figure 5.4 Final stage of synthesis of fluoxetine in manufacturing route
• Figure 5.5 The stages of pharmaceutical discovery and development
• Figure 5.6 Image of an infusion bag prepared for intravenous administration
• Figure 5.7 Schematic to show timing of major drug safety studies
• Figure 5.8 Illustration of a typical 28 day drug safety protocol
• Figure 5.9 Example of toxicokinetic data constructed from blood samples taken on Days 1 and 28 of a multiple dose safety study
• Figure 5.10 Comparison of toxicokinetics in rats and dogs
• Figure 5.11 Temporal arrangement of safety studies during the first 3-4 years of development
• Figure 5.12 Summary of the three aspects of reproductive toxicology
• Figure 5.13 Sample protocol for EFD study in the rat
• Figure 5.14 Chromosomal matching and identification of aberration in CHO cells
• Figure 5.15 Sigmoid - S-shaped - dose/response curve
• Figure 5.16 Schematic to show potential ADME fates of absorbed drugs
• Figure 5.17 An illustration of plasma protein binding
• Figure 5.18 Metabolic map containing a [14]C label in a metabolically stable position. Major metabolites can now be tracked and quantified through the determination of radioactive emissions
• Figure 5.19 Fundamental principles of a mass balance study using a radio-labelled drug substance
• Figure 5.20 Illustration of HMG CoA RI drug absorption through GI wall and return in the bile
• Figure 5.21 The eternal triangle revisited
• Figure 6.1 Comparative effects of an NME and budesonide for their ability to induce vasoconstriction in human forearm skin
• Figure 6.2 Graphs to show effects of PDE4 inhibitor upon TNFa generation and the induction of nausea
• Figure 8.1 Comparison of US and UK regulatory procedures before May 2004
• Figure 8.2 Four levels of application recognised by the EMEA to market new medical products
• Figure 8.3 Generic format of the common technical document
• Figure 10.1 The changing emphasis of drug safety responsibilities