1. Drug Discovery Process
BIT 120

3. 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.

4. 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

5. Find chemical which inhibits this enzyme DRUG CANDIDATE
Animal Studies
(preclinical studies)

6. 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)

7. 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

8. Timeline for Discovery and Development
A. Laboratory and animal studies 6 yrs
B. File Investigational New Drug (IND)
to FDA
C. Phases I- III years
D. File New Drug Application (NDA)
at FDA: years
E. Phase IV (post approval) 6 years

9. IND components – Goes into effect after 30 days if FDA says nothing
Clinical Trials
IND components – Goes into effect after 30 days if FDA says nothing
Previous experiments
Chemical structure
Toxicity in animals

10. Purpose Is drug SAFE AND EFFECTIVE??? Predict Toxic Effects
Determine Safe Dosage
Determine efficacy (effectiveness)

11. Participant in trial
Entry criteria – age, sex, smoking status, other meds
Big cities
Sign a consent form
Voluntary – can withdraw anytime
Confidentiality
Often paid

12. $500 million/drug (dropping due to genomics)
Cost
Cost:
$500 million/drug (dropping due to genomics)
Success Rate
5000 : 1
Total time
15 years chemical drug
10 years biological drug

13. 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
years

14. Pharmacokinetics How drug is: Absorbed Metabolized Excreted
Duration of action

15. Phase II larger group of people (100-300) people with disease
effectiveness
further evaluate its safety
dosage
2 years

16. 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

17. 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

18. Launch Drug

19. 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)

20. 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

21. Placebo When don’t you use a placebo?
Drug available already to treat disease
Unethical to use placebo

22. Discovery:
Good Laboratory Practices (GLP)
Development:
Good Manufacturing Practices (GMP)
Standard Operating Practices (SOP)
Documentation, Documentation, Documentation