Drug Discovery/ PD & PK

• Current Approaches to New Drug Discovery

  • Screening for biologic activity
  • Chemical modification of a known molecule
  • Rational drug design
  • Biotechnology & recombinant DNA techniques
  • New drug target
  • Combinations of known drugs to obtain additive or synergistic effects or a repurposing of a known drug for a new therapeutic use
• Methods for developing chosen leads: Compound-based Approach


  1. Naturally occurring products
  2. Ex) Digitoxin from Digitalis purpurea
  3. Purely synthetic drugs
  4. Ex) Hycamptin from camptothecin
  5. Drug metabolites
  6. Ex) Fexofenadine, a metabolite from terfenadine
• Methods for developing chosen leads: Target-based Approach 


  1. Systemic approach to identifying targets
  2. Screening method
• Target-based Approach

  • Systemic approach to identifying targets:
  • Mechanisms of disease
  • Life processes of pathogens
  • Hypothesis related to the target
  • the development of protease inhibitors for treatment of HIV
  • $\beta$-adrenergic antagonists for hypertension
  • $\beta$-adrenergic agonists for asthma
• Target-based Approach

  • Screening method
  • Combinational chemistry

  
• Target-based Approach


  • Screening method
  • High throughput screening
  • Allows a researcher to quickly conduct millions of chemical, genetic, or pharmacological tests.
  • Using robotics, data processing/control software, liquid handling devices, and sensitive detectors
  • Recognize active compounds, antibodies, or genes that modulate a bimolecular pathway
  • Results provide starting points for drug design
  • The key labware for HTS is the microtiter plate
  • Reaction wells in multiples of 96 (192, 384, 1536 etc.)

  
• Screening for activity of chosen leads:

  1. In vitro studies ("within the glass")
  2. cell membranes
  3. more complicated cell-based systems
  4. Functional selectivity leads to a high probability of false negatives and positives
  5. In vivo studies ("within the living")
  6. After the drug is tested at the molecular level, it needs to be tested in the animal as a whole.
• The main characteristics of good therapeutic agents:

  1. Effective (Efficacy)
  2. Selective (Affinity) in activity
  3. Delivered to site of action
  4. Good Pharmacokinetics – ADME
  5. No side effects in all patients – race/genetic polymorphisms
  6. Good physicochemical properties - Easy to formulate and administer
• A: Preclinical Studies 


  • Large scale synthesis and physicochemical properties
  • Stability and shelf-life
  • ADME
  • Degradation products
  • Formulation(s)
  • Toxicity studies (acute, chronic and single overdose) in two animal models
  • New FDA rule in 2022 – no longer needs to require animal tests

  A) In vitro

  B) Animal

  
• B: Investigational New Drug (IND)


  • The FDA’s Center for Drug Evaluation (CDER) evaluates the application and decides within 30 days
  • IND approval authorizes start of clinical trials

  A) IND

  
• C: Phase 1 Clinical Trials (~1 year)

  • To determine SAFETY
  • 20 - 100 healthy volunteers (18-65 yrs)
  • Evaluate maximum tolerated dose and pharmacokinetics (ADME

  
• D: Phase 2 Clinical Trials (up to 2 years)

  • To determine efficacy (testing in patients)
  • 100 - 200 patients with disease
  • Effect in patients (single blinded), side effects etc.
  • FDA helps decide whether to continue with trials (a lot of drugs fail here)

  
• E: Phase 3 Clinical Trials (up to 4 years)

  • To confirm efficacy, optimize dosing
  • 1000 - 6000 patients with disease in multiple clinical sites
  • Evaluate double-blinded study results, side effects and PK
  • FDA helps decide whether to continue with trials

  
• F: New Drug Application (NDA)


  • Manufacturing specifics
  • Stability and bioavailability data
  • Methods of analysis of each of the dosage forms
  • Packaging and labeling for physicians and consumers
  • Any new toxicology data since IND
  • NDA APPROVED – DRUG GOES TO MARKET !!!!

  
• G: Post-marketing Surveillance 


  • Safety-First Initiative by the FDA
  • Post-marketing surveillance to determine if any previouslyunrecognized adverse effects have occurred.
  • FDA may require additional clinical studies to clarify aspects of the drug effects

  A) Marketing

  
• Target-based Approach


  • Screening method
  • Computer aided drug design
  • Saves time, money, resources
  • Ex) screening for a novel TGF−β1TGF−β1 receptor kinase inhibitor

  
• Drug discovery to FDA approval

  A) 10,000

  B) 250

  C) 5

  D) 1

  
• FDA Drug Review Categories: Fast Track


  Fast track is a process designed to facilitate development, & expedite the review of drugs to treat serious conditions and fill an unmet medical need. The purpose is to get a new drug to the patient quicker.
• A drug that receives Fast Track designation is eligible for:

  • More frequent meetings and communication with the FDA
  • Eligibility for Accelerated Approval and Priority Review
  • Rolling Review = drug company can submit completed sections of its Biologic License Application (BLA) or New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be reviewed.
• FDA Drug Review Categories: Breakthrough Therapy 


  A process designed to expedite the development and review of drugs which may demonstrate substantial improvement over available therapy.

  • Clinically significant endpoint generally refers to an endpoint that measures an effect on irreversible morbidity or mortality (IMM)
• Surrogate Endpoint


  In clinical trials, a surrogate endpoint is a measure of effect of a specific treatment that may correlate with a real clinical endpoint but does not necessarily have a guaranteed relationship.
• FDA Drug Review Categories: Accelerated Approval 


  These regulations allow drugs for serious conditions that filled that fill an unmet medical need to be approved based on a surrogate endpoint.

  • A surrogate endpoint used for accelerated approval is a marker - a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit.
  • Phase 4 confirmatory trials
• FDA Drug Review Categories: Priority Review 


  A Priority Review designation means the FDA's goal is to take action on an application within 6 months.

  • It does not affect the length of the clinical trial period.
  • FDA set specific goals for improving the drug review time and created a two-tiered system of review times = Standard Review and Priority Review.
• Orphan Drugs

  Orphan Drug Act (ODA) 1983 — legislation that incentivized drug companies to put more resources toward the research, development, and distribution of therapeutics for people with rare diseases, who until then had been ‘orphaned’ by the medical and scientific community.

  • Orphan drug designation qualifies sponsors for incentives including:
  • Tax credits for qualified clinical trials
  • Exemption from user fees
  • Potential seven years of market exclusivity after approval
  • Designation is a separate process from seeking approval or licensing
• Generic Drugs


  FDA's Office of Generic Drugs (OGD) within the Center for Drug Evaluation and Research ensures high-quality, affordable generic drugs are available.

  Review process includes:

  • Managing the regulatory process to facilitate drug approvals,
  • Establishing science initiatives to research generic drugs,
  • Publishing data and reports on generic drug development and review, and
  • Offering educational materials and information
• Abbreviated New Drug Application (ANDA)

  Generic drug applications are termed "abbreviated" because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.
• Drug Absorption

  Systemically administered drug may be absorbed directly from site of administration (skin) or from a distant site (oral)

  • Regardless,
  • Drug must be dissolved in body fluid
  • Drug needs to cross epithelial barrier at absorption to enter the bloodstream
• Factors Controlling Drug Absorption

  1. Solubility of the drug
  2. Dissolution rate
  3. Concentration
  4. Circulation at the site of absorption
  5. Surface area of absorbing site
• Oral Route of Administration


  • Most common route, preferred, and safest
  • Influenced by pH (1 - 3) of stomach
  • Stomach is site of dissolution/degradation
  • Little absorption due to limited time of drug in stomach
  • Small intestine (6-7 m in length) is the major site of absorption due to enormous surface area
  • Large intestine (1.5 m) mostly involved in absorption of water and electrolytes from feces
  • Subject to first-pass effect
• Buccal or Sublingual Route of Administration


  • Drug is placed under tongue or crushed and spread in the buccal area
  • Absorption is quick
  • Avoids first-pass metabolism
  • Suitable for drugs destroyed by stomach acid and enzymes
  • Rapid absorption of lipophilic drugs by transcellular diffusion
  • Unsuitable for bitter tasting drugs
• Rectal Route of Administration




  • Drugs are rectally administered by suppository or retention enema
  • Limited absorption due to lower surface area
  • Advantages
  • Pediatrics
  • Largely avoids first-pass metabolism
  • Disadvantages
  • Slow, incomplete and irregular absorption
  • Irritation of rectal mucosa can occur
• Parenteral Routes of Administration

  1. Subcutaneous (SC or SQ)
  2. Slow absorption, prolonged action
  3. Intramuscular (IM)
  4. Most common parenteral route
  5. Fairly rapid absorption
  6. Intravenous (IV)
  7. Most rapid, dangerous
  8. Intraperitoneal (IP)
  9. Injected into abdominal cavity
  10. Intradermal
  11. Injected under epidermis -- some vaccines
• Transdermal Route of Administration


  • Absorption of drug through intact skin
  • Drug absorption may be facilitated by carriers and devices
  • Fairly constant delivery of drug
  • Nicotine patches for treatment of addiction
  • Fentanyl patches for pain therapy
  • Hormone therapy
  • Slow process and used for long- term therapy
  • Iontophoresis: local electric current drives ionic drugs across skin
• Nasal Route of Administration



  • Absorption of drug through the nasal mucosa
  • Rapid drug absorption
  • Attractive for small proteins and other macromolecules that cannot be given by oral route
  • Disadvantages
  • Limited surface area
  • Limited doses
  • Damage to nasal lining with long-term use
• Pulmonary Route of Administration

  • Drug inhaled by mouth into the lungs
  • Absorption is through passive diffusion across the alveolar epithelium
  • Drug must reach the terminal bronchioles and alveoli to be effectively absorbed
  • Particles less than 5 μm in diameter are preferred
  • Dosage form, retention and clearance from lung can be problematic
• Drug Distribution

  A) Unbound

  B) Bound

  C) Metabolism

  D) Receptors

  E) Elimination

  
• Drug Distribution

  • The reversible transfer of drug between the vascular space and extravascular space
  • Distribution of drug is uneven due to differences in regional pH, blood perfusion, protein and tissue binding, membrane permeability and drug characteristics
• Drug Distribution

  • Drug concentration in interstitial fluid (ISF) will = free drug concentration in plasma @ equilibrium
  • Free drug in ISF may enter tissue cells and be distributed in a larger volume than drug that remains in plasma or ISF
  • Apparent volume of distribution (Vd)
  • Small for drugs that remain mostly in plasma
  • Large for drugs that distribute in plasma+ISF+ICF

  
• Protein Binding


  • Reversible binding to plasma proteins (mainly albumin) forms drug-protein complexes
  • Binding depends on concentration of drug, number of binding sites available and association constant between drug and protein
  • Binding can vary from 0 - 99% and influences the half-life of the drug

  
• Tissue Binding


  • Drug binding to tissue components can result in a large Vd
  • Tissue binding may be a slow process and become evident only after the drug has equilibrated in all fluids and reached a steady state
  • Tissue binding leads to “storage” such as in adipose (fat) tissue
  • Vd for drugs binding to tissue may be much higher than total body water
  • Tetracycline antibiotic
  • Deposited in teeth and bones due to chelation with divalent calcium at these sites