Drug Discovery and Development Flashcards
List the factors in History of Modern Drug Discovery. ~~~~
- 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
Steps to Modern Drug Discovery ~~~~
- Disease Pathology and Target
- Target Identification
- Assay Development
- Hit to Lead Compounds
- Lead Optimization
- Preclinical Development
- Clinical Trials
Molecular Targets leading to Disease
Bacterial Infection: host imbalance
The Methods of Drug Discovery
- Random untargeted screening
- High-throughput screening
- Molecular modification of known agents
- Mechanism-based drug design
Describe the Drug Development Process
- New Therapeutic Molecule
- Preclinical Testing (ADME)
- IND Application
4a. Clinical Trials (Phase 1-3)
4b. Research and Development - NDA
- FDA Approval and Post-marketing surveillance (Phase 4)
Drug Development Process—Timeline ~~~~~~
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
- 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
Recombinant DNA technology (biological drug development process)
- 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
Monoclonal Antibody (mAb) Technology (biological drug development process)
-has the potential to be used to prevent, treat, cure, diagnose, or mitigate human disease caused by genetic factors
Gene Therapy
Define Antisense therapy
The use of antisense compounds to prevent the transcription or translation of DNA to treat specific diseases
BLAs
- What are they? - Who are they submitted to?
- Biologics License Application
- Submit to CBER
CBER
Center for Biologics Evaluation and Research
-for manufacturing of Biologics
- Blood and Blood components/products
- Vaccines
- Toxins
BLAs are submitted to CBER for manufacturing of these products
Structure, synthesis, purity, isomers, pKa, stability, and solubility
Chemical characterization during Preclinical testing
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)
Biological characterization during Preclinical testing
Equation for Therapeutic Index
Lethal Dose in 50% Subjects (LD50)
=_________________________________________
Effective Dose in 50% Subjects (ED50)
ADME/Tox and what it is used for
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
What is the purpose of Pre-formulation Studies? What do they define? (List)
Purpose: to define the physical and chemical properties of the agent
- Drug solubility and pH
- partition coefficient
- physical forms
- particle size
- stability
Factors that affect drug solubility and pH
Salts or esters, chemical complexation, reduction in drug’s particle size (increases solubility)
Indicates a drugs ability to penetrate biological membranes
Partition Coefficient
The physical forms of drugs
Crystals, amorphous or polymorphic
How does reduction of particle size affect dissolution and absorption
Reduction in particle size increases surface area, which increases in drug’s dissolution rate and absorption
Why is stability of the drug important in pre-formulation studies?
- For drugs susceptible to oxidative decomposition
- for drugs destroyed by hydrolysis
Safe and effective dose of a drug depends on: (list)
- 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*
What are some of the things regulated by the FDA
Drugs, Biologics, medical devices, food, animal feed and drugs, cosmetics, electromagnetic radiation
Who reviews and approves IND applications?
IBR (institutional review board)
After IRB approval of IND, what is the next step?
FDA Review of IND by either the
- CDER (Center for Drug Evaluation and Research) - CBER (Center for Biologics Evaluation and Research)
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?
- CDER
- Involved in Phase 1 after approval of IND
- After Phase 3: marketing applications (NDAs and BLAs)
What are the marketing applications for Biologics and synthetics
Synthetics: NDA (new drug application)
Biologics: BLA (biologic license application)
Phase 1 objectives in Clinical Trials (list at least 3)
- metabolic and excretory pathways
- variability between individuals; effect of route on bioavailability
- tolerated dose range
- indication of therapeutic effects
- indication of side effects
Phase 2 objectives of Clinical Trials (list at least 3)
- 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
Phase 3 clinical trial objectives (list at lease 3)
- 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
where neither the researchers nor the patients know what they are getting; computer assigns patients code numbers; code numbers are allocated to treatment groups
Double Blind Trial
Phase 4 and Post marketing surveillance objectives (list at least 3)
- 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:
- Issue special warning notices
- Review of available clinical data
- Withdraw approval for marketing
Must meet specific labeling requirements in CFR and approved for each product by the FDA. What are the things it must include?
Drug Product Labeling
- Package insert
- Company literature
- Advertising
- Promotional materials
CFR
Code of Federal Regulations
What is a SNDA and its purpose?
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
Chemical equivalents of drugs whose patents have expired
Generic Drug
FDA requirements for generic drugs and the application
-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
