Lecture 1: Drug Overview Flashcards
What was important for human-based screening?
Medicinal plants
What was important for animal-based screening?
Anesthetics
What was important for bacteria-based screening?
Penicillin
What was important for tissue-based screening?
G protein-coupled receptor
What was important for target-based screening?
High throughput screening
What was important for mechanism/structure based?
HIV
What was important for molecular and cellular based?
Kinase inhibitors
What was important for genomics based patient profiling?
MiRNA profiling and RNA sequencing
What are the steps to modern drug discovery?
- Disease pathology and target
- Target identification
- Assay development
- Hit to lead compounds
- Lead optimization
- Preclinical development
- Clinical trials
What are four methods of drug discovery?
- random untargeted screening
- high-throughput screening
- molecular modification of known agents
- mechanism-based drug design
What are different sources of a new therapeutic molecule?
- extraction from plants
- organic synthesis
- animals
- genetic engineering
- gene and cell therapy
What is the purpose of gene therapy?
To synthesize a protein inside the body
What is antisense therapy?
When you do not want the protein in gene therapy, so you want to inhibit it
Can block transcription, translation or inactivate the protein
What does BLAs stand for?
Biologics License Application
What does CBER stand for?
Center for Biologics Evaluation and Research
Where is the BLAs submitted to?
CBER for manufacturing of biologics such as blood and blood components used for infusion or derived pharmaceutical products such as clotting factors
Vaccines or toxins
What is part of preclinical testing?
Chemical and biological characterization
What is part of chemical characterization of preclinical testing?
Structure Synthesis Purity Isomers PKa Stability Solubility
What is part of the biological characterization of preclinical testing?
Acute pharmacological profile (LD50, ED50)
Receptor binding
Dose-effect relationships
Tests for different activities
What is the therapeutic index calculation?
Lethal dose in 50% of subjects (LD50) / Effective dose in 50% subjects (ED 50)
What is the ADME/Tox?
Absorption Distribution Metabolism Excretion Toxicology prediction
What is important during preclinical testing?
Safety and toxicity in animals
What profiles are part of the safety and toxicity in animals?
- acute toxicity profile
- chronic toxicity profile
- toxicity test in rodents and non-rodents before humans
- toxicity at dose levels below, about, well above human dose
What aspect of pharmacy is important during preclinical testing?
Pharmacokinetics and pharmacodynamics
Before the drug is created, what must be done?
Pre-formulation studies
What is the purpose of pre-formulation studies?
To define the physical and chemical properties of the agent
What is key to consider before formulation of the drug?
The drug solubility and pH
What are commonly used approaches to increase the drug solubility and pH?
- make salts
- make esters
- form chemical complexation
- reduce particle size in drugs
What does increasing the drug’s solubility do?
Increase the absorption
What is the difference between a crystal vs amorphous form ?
Crystals are less soluble
What does a reduction in particle size do to the drug?
Increases the surface area
Increases the drug’s dissolution rate and absorption
What happens for drugs that are susceptible to oxidative decomposition?
Degrade, so then need to add an antioxidant
What happens to drugs that are destroyed by hydrolysis?
Cannot add by injection
Need to be reconstituted right before injection because they are unstable in water
What do you check during the pre-formulation studies?
- drug solubility and pH
- partition coefficient
- physical forms
- particle size
- stability
What does a drug’s partition coefficient indicate?
Its ability to penetrate biological membranes
What factors are integral to clinical trials?
Physicochemical properties of a drug Dosage forms Route of administration Patient condition, age, gender, disease status Concomitant drug therapy
What does safe and effective dose of a drug depend on?
Physiocochemical properties of a drug Dosage forms Route of administration Patient condition, age, gender, disease status Concomitant drug therapy
What dose FDA stand for?
Food and Drug Administration
What phase of clinical trials has healthy volunteers and has 20-100 people?
Phase I
What phase of clinical trials has a small number of patients and has up to several hundreds of people?
Phase 2
What phase of clinical trials has a large scale multi-centers?
Phase 3
What phase of clinical trials has post marketing monitoring, several hundreds to several thousands of people?
Phase 4
What dose IRB stand for?
Institutional Review Board
What must occur before any clinical testing?
Review and approval of an IND application by IRB
What are two important FDA centers that review an IND application?
CDER &CBER
What does CDER stand for?
Center for Drug Evaluation and Research
What does CBER stand for?
Center for Biologic Evaluation and Research
What is a double blind trial?
Neither researcher nor patients know what they are getting
Computer gives each patient a code and code numbers are allocated to treatment groups
What does SNDA stand for?
Supplemental New Drug Application
What does ANDA stand for?
Abbreviated New Drug Application
What are generic drugs?
Chemical equivalent of drugs whose patents have expired
What does NDA stand for?
New Drug Application
