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 D. File New Drug Application (NDA) at FDA: E. Phase IV (post approval) 7 years 1.5 years 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