Download Drug Discovery Process

Drug Discovery Process
BIT 120
ACE Inhibitors
Angiotensin Converting Enzyme (ACE)
causes constriction of blood vessels by converting
angiotensin from inactive to active form – want to
block this enzyme, so blood vessels relax (Better
blood flow, lower b.p.)
Look for inhibitors to other ACE proteins
Class of drugs – end in “pril” – Captopril, etc.
Discovery Process
Pre-Clinical
Search Public Genome Databases for similar (homologous)
sequences to original ACE gene
Take these snippets and hybridize with genetic material from
different tissues
Matches LIGHT up.
Clone the genes that light up
Find chemical which inhibits this enzyme
DRUG CANDIDATE
Animal Studies
(preclinical studies)
Some considerations
• Look at safety in animals – large doses and
long term
• Chronic – long term- asthma, hypertension
(need to take drug for life)
• Acute – short term – for short term illness
(e.g., bacterial infection, take antibiotic for
10 days)
Animal Models
Knockout Mice
disrupt gene by deliberate mutation – gene blocked at
embryo stage
Problems
•Animals may not get disease we get (HIV)
•Model does not mimic human condition
(good model – athero and pigs)
•PETA – people for the ethical treatment of animals
Timeline for Discovery and
Development
A. Laboratory and animal studies
6 yrs
B. File Investigational New Drug (IND)
to FDA
C. Phases I- III
7 years
D. File New Drug Application (NDA)
at FDA:
1.5 years
E. Phase IV (post approval)
6 years
Clinical Trials
IND components – Goes into effect
after 30 days if FDA says nothing
Previous experiments
Chemical structure
Toxicity in animals
Purpose
Is drug SAFE AND EFFECTIVE???
•Predict Toxic Effects
•Determine Safe Dosage
•Determine efficacy (effectiveness)
Participant in trial
• Entry criteria – age, sex, smoking status,
other meds
• Big cities
• Sign a consent form
• Voluntary – can withdraw anytime
• Confidentiality
• Often paid
Cost
Cost:
$500 million/drug (dropping due to genomics)
Success Rate
5000 : 1
Total time
15 years chemical drug
10 years biological drug
Phase I
•small group of people (20-80)
•individuals do NOT have disease
•evaluate its safety; common side effects:
•Fatigue, nausea, hair loss, vomiting
•determine a safe dosage range
•identify side effects
•0.5-1.5 years
Pharmacokinetics
• How drug is:
– Absorbed
– Metabolized
– Excreted
– Duration of action
Phase II
•larger group of people (100-300)
• people with disease
•effectiveness
•further evaluate its safety
•dosage
•2 years
Phase III
•large groups of people (1,000-3,000)
•to confirm its effectiveness
•monitor side effects
•compare it to commonly used treatments
•Interactions (with other meds)
•Multicenter trial – many docs; many
hospitals
Phase III
• May be vs. placebo:
• Placebo effect: measurable, desirable effect;
patients don’t know if on drug or placebo
• Patient feels better even if on placebo
– Often seen with antidepressants, antianxiety
meds
Launch Drug
Phase IV
•after the drug or treatment has been marketed
•collect information about their effect in various
populations
•side effects associated with long-term use.
•New indications: impt for company to extend its
patent protection.
•Eg. Prozac – antianxiety, approved recently for
PMDD (premenstrual dysorphic disorder)
Issues
Pharmacokinetics
how quickly drug is absorbed
eliminated from body (clearance)
Delivery Problem – injection vs. oral delivery
Do patients develop tolerance?
Pharmacogenetics
Interfere with meds for other diseases – eg. Lower bp
but interfere with med for type II diabetes
Placebo
• When don’t you use a placebo?
• Drug available already to treat disease
• Unethical to use placebo
Discovery:
Good Laboratory Practices (GLP)
Development:
Good Manufacturing Practices (GMP)
Standard Operating Practices (SOP)
Documentation, Documentation, Documentation