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Pharm Sci > Drug Discovery and Development > Flashcards

Drug Discovery and Development Flashcards

1
Q

List the factors in History of Modern Drug Discovery. ~~~~

A
  • Human-based screening: medicinal plants
  • Animal-based screening: anesthetics
  • Bacteria -based screening: penicillin
  • Tissue-based screening: GPRC
  • Target-based screening: High Throughput screening
  • Mechanism/structure-based: HIV
  • Molecular and cell based: kinase inhibitors
  • Genomics-based patient profiling: mRNA profiling, RNA sequencing
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2
Q

Steps to Modern Drug Discovery ~~~~

A
  1. Disease Pathology and Target
  2. Target Identification
  3. Assay Development
  4. Hit to Lead Compounds
  5. Lead Optimization
  6. Preclinical Development
  7. Clinical Trials
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3
Q

Molecular Targets leading to Disease

A

Bacterial Infection: host imbalance

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4
Q

The Methods of Drug Discovery

A
  • Random untargeted screening
  • High-throughput screening
  • Molecular modification of known agents
  • Mechanism-based drug design
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5
Q

Describe the Drug Development Process

A
  1. New Therapeutic Molecule
  2. Preclinical Testing (ADME)
  3. IND Application
    4a. Clinical Trials (Phase 1-3)
    4b. Research and Development
  4. NDA
  5. FDA Approval and Post-marketing surveillance (Phase 4)
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6
Q

Drug Development Process—Timeline ~~~~~~

A

Preclinical Testing
-Synthesis: identify a lead compound’
-Characterization: physiochemical properties
-Toxicity and Bioactivity: in vitro (cell culture) and in vivo (short
term)
-ADME/Tox
~Avg: 3.5 years
~Evaluation of thousands of compounds
IND submission*
Clinical Trials, Research and Development
-Phase I: healthy volunteers (20-80), safety profiles, drug tolerances
-Phase II: Patients (100-300), controlled, randomized trials, double-
blinded, short-term side effects, decision on final dosage form
-Phase III: Patients (1000-3000), expanded and uncontrolled trials,
Monitor adverse rxns, confirm effectiveness, decision on physician
Labeling
~Avg. 1.5+2+4=7.5 years
~<1% enter trails
**NDA Filing*****
FDA
-Review and Approval
~6-10 months
~1 Approved
Post marketing Surveillance
-Phase 4: postmarketing testing, report adverse effects, report
dosage defects

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7
Q
  • has the potential to produce a variety of proteins
  • involves protein production within the cells of lower animals
  • ex: human insulin, human growth hormone, interferon
A

Recombinant DNA technology (biological drug development process)

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8
Q
  • specificity binds to target cells or proteins, when then stimulate the patient’s immune system to attack those cells
  • has the potential to produce a desired antibody
  • antibody production is conducted entirely within the cells of higher animals including the patient
  • can treat: MS, RA, Alzheimer’s
A

Monoclonal Antibody (mAb) Technology (biological drug development process)

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9
Q

-has the potential to be used to prevent, treat, cure, diagnose, or mitigate human disease caused by genetic factors

A

Gene Therapy

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10
Q

Define Antisense therapy

A

The use of antisense compounds to prevent the transcription or translation of DNA to treat specific diseases

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11
Q

BLAs

 - What are they?
 - Who are they submitted to?
A
  • Biologics License Application

- Submit to CBER

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12
Q

CBER

A

Center for Biologics Evaluation and Research

-for manufacturing of Biologics

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13
Q
  1. Blood and Blood components/products
  2. Vaccines
  3. Toxins
A

BLAs are submitted to CBER for manufacturing of these products

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14
Q

Structure, synthesis, purity, isomers, pKa, stability, and solubility

A

Chemical characterization during Preclinical testing

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15
Q

acute pharmacological profile— LD50, ED50, receptor binding, dose-effect relationships, tests for different activities (such as Chorionic villus sampling (CVS) for chromosome and genetic disorders, CNS, GI tract)

A

Biological characterization during Preclinical testing

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16
Q

Equation for Therapeutic Index

A

Lethal Dose in 50% Subjects (LD50)
=_________________________________________
Effective Dose in 50% Subjects (ED50)

17
Q

ADME/Tox and what it is used for

A

Absorption, Distribution, Metabolism, Excretion, and Toxicology prediction

Used in preclinical testing to determine safety and toxicity in animals and to develop

 - acute toxicity profile
 - chronic toxicity profile
 - toxicity test in rodent and non-rodent species before use in humans
 - toxicity at dose levels below, about, well above human dose
18
Q

What is the purpose of Pre-formulation Studies? What do they define? (List)

A

Purpose: to define the physical and chemical properties of the agent

  • Drug solubility and pH
  • partition coefficient
  • physical forms
  • particle size
  • stability
19
Q

Factors that affect drug solubility and pH

A

Salts or esters, chemical complexation, reduction in drug’s particle size (increases solubility)

20
Q

Indicates a drugs ability to penetrate biological membranes

A

Partition Coefficient

21
Q

The physical forms of drugs

A

Crystals, amorphous or polymorphic

22
Q

How does reduction of particle size affect dissolution and absorption

A

Reduction in particle size increases surface area, which increases in drug’s dissolution rate and absorption

23
Q

Why is stability of the drug important in pre-formulation studies?

A
  • For drugs susceptible to oxidative decomposition

- for drugs destroyed by hydrolysis

24
Q

Safe and effective dose of a drug depends on: (list)

A
  • Physicochemical properties of a drug
  • Dosage forms
  • Route of administration
  • Patient condition age, gender, disease status
  • Concomitant drug therapy
    • All of these factors are integral to clinical trials*
25
Q

What are some of the things regulated by the FDA

A

Drugs, Biologics, medical devices, food, animal feed and drugs, cosmetics, electromagnetic radiation

26
Q

Who reviews and approves IND applications?

A

IBR (institutional review board)

27
Q

After IRB approval of IND, what is the next step?

A

FDA Review of IND by either the

 - CDER (Center for Drug Evaluation and Research)
 - CBER (Center for Biologics Evaluation and Research)
28
Q

What organization oversees research, development, manufacture, and marketing of all small MW drugs and biological therapeutic agents? When are they involved in the clinical trials?

A
  • CDER
  • Involved in Phase 1 after approval of IND
  • After Phase 3: marketing applications (NDAs and BLAs)
29
Q

What are the marketing applications for Biologics and synthetics

A

Synthetics: NDA (new drug application)
Biologics: BLA (biologic license application)

30
Q

Phase 1 objectives in Clinical Trials (list at least 3)

A
  • metabolic and excretory pathways
  • variability between individuals; effect of route on bioavailability
  • tolerated dose range
  • indication of therapeutic effects
  • indication of side effects
31
Q

Phase 2 objectives of Clinical Trials (list at least 3)

A
  • 150-300 patients; informed consent needed
  • maximum monitoring
  • often patients where other treatment failed
  • dose range depends on type of patient and severity of disease
  • pharmacokinetic studies in patients
  • nature of side effects and severity
  • effects in special groups
32
Q

Phase 3 clinical trial objectives (list at lease 3)

A
  • 1500-3500 patients at multi-centers
  • more certain data for efficacy and toxicity
  • drug-drug interactions to become measurable in the larger population
  • sub-groups start to be established
  • special features and problems show up
33
Q

where neither the researchers nor the patients know what they are getting; computer assigns patients code numbers; code numbers are allocated to treatment groups

A

Double Blind Trial

34
Q

Phase 4 and Post marketing surveillance objectives (list at least 3)

A
  • Adverse drug experiences must be reported to the FDA within 15 working days of receipt of information
    1. Serious adverse effects
    2. Unexpected adverse effects
  • FDA may revise product labeling
  • Other actions:
    1. Issue special warning notices
    2. Review of available clinical data
    3. Withdraw approval for marketing
35
Q

Must meet specific labeling requirements in CFR and approved for each product by the FDA. What are the things it must include?

A

Drug Product Labeling

  1. Package insert
  2. Company literature
  3. Advertising
  4. Promotional materials
36
Q

CFR

A

Code of Federal Regulations

37
Q

What is a SNDA and its purpose?

A

Supplemental New Drug Application
-For an Approved NDA, Spenser may make changes for a
number of reasons
1. Change in method of synthesis
2. Change of manufacturing facilities
3. Change in formulation
4. Minor changes can be made without prior approval

38
Q

Chemical equivalents of drugs whose patents have expired

A

Generic Drug

39
Q

FDA requirements for generic drugs and the application

A

-Scientific evidence that the generic is interchangeable with or therapeutically equivalent to the original
ANDA: Abbreviated New Drug Application

  • Review based on bio equivalence and manufacturing control.
  • Equivalent in terns of bioavailability, ADME, and Tox
  • Nonclinical and clinical studies may be omitted

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