CH1: Drug Discovery, Development, Naming, & classification

Which disease is chosen to have R&D

pharm companies choose a disease that targets a large market, orphan diseases often missed or incentivized with grants

R&D for one drug cost

$2.25B

Problems with Drug Therapy

1. Innovation driven by $ AND financial incentives NOT pt interest

2. High cost = access issue

3. Trade-offs: old drugs cheaper but less effective

drug target

biological target molecule that the drug will interact with

Biological target examples

receptor, enzyme, hormones & factors, ion channels, DNA, RNA, other proteins

selectivity

ability of the drug to ID the target vs. everything else in the body that is not the target.

amount of ____ of a drug determines amount of side effects

selectivity

lead compound

first compound having desired target activity

Finding a lead compound through

natural products, chemical banks, rational drug design

____ is used to optimize lead compound by ____

organic chem; adding different functional groups

How to optimize lead compound

1. test variants, select best performer, repeat
   

2. identify and remove non-essential functional groups

3. outcome: optimized drug candidate for clin trial

Rational drug design

process of finding a lead compound by utilizing the side effect of known drug or altering a natural ligand.

Thalidomide Tragedy

Marketed (sedative) morning sickness drug that cause severe birth defects for pregnant women in Europe (and US even though it wasnt approved)

Kefauver-Harris Amendment

requires substantial scientific evidence that a drug is safe and effective to treat a specific condition, FDA approval prior to marketing to providers, & informed consent for patients participating in clinical trails

Dietary Supplement Health and Education Act (DSHEA)

1. defines dietary supplement labeling rules

2. no FDA approval required

3. FDA only acts if unsafe/mislabeled

Comprehensive Drug abuse prevention and control act

Special DEA license required to prescribe opiods

A drug is safe to be OTC if it ...

1. has a wide margin of safety

2. consumer-friendly use and instructions

3. condition easily self-diagnosed by consumer

4. low risk for misuse or abuse

(FDA must approve before marketing)

Major steps in drug approval process

1. Preclinical studies

2. Investigational new drug (IND) application filed

3. Clinical trials (1, 2, 3)

4. New drug application filed

5. Drug marketed to providers and public

6. Phase IV post-market studies

phase I clinical trials

drug is tested on healthy humans to assess safety and initial dosing

(is it safe to move on?)

(10-100ppl)

phase II clinical trials

drug is tested on humans with dz to assess efficacy and dose optimization

(does it work and still safe?)

(50-500pts)

phase III clinical trials

drug is tested in comparison to a placebo on large pt populations across multiple sites to confirm efficacy and monitor safety

(Does it work better than standard/placebo?)

(100s-1000s pts)

phase IV clinical trials

post-marketing surveillance for safety and rarer side effects

(What happens in real-world use?)

On label use of drugs

drug is used exactly as approved by FDA

Off label use of drugs

Any use of drug not listed on FDA label. Pts must be informed when using drugs off label

Off-label use is:

Common

Evidence Based

Used when better options unavailable

Boxed warnings

FDA's strongest safety warning for a prescription drug

boxed warnings used___

when a drug carries serious adverse effects and life-threatening complications and death

Drug Nomenclature

1. Chemical Name (chm) _early discov.

2. Code Name (#) -research ID

3. Non-proprietary (generic) -during clinical trials

4. Proprietary (brand) -created after approval for marketing

brand name drugs are___

patent protected for 20 yrs + higher cost to recover R&D cost

Small molecule drugs

1. small, organic

2. able to diffuse across cell membranes

3. low molecular weight

4. simple structure that is well defined and easier to manufacture

majority of drugs currently on the market are ___ drugs as they are easily ____ and ____ copies can be made

small molecule; reproducible; identical

Biological drugs

1. large/ composed of protein, sugars, nucleic acids, living cells or tissues

2. high molecular weight

2. complex and not easily defined structures

3. highly specific

Biologics are not identical because

made in living systems/ complex & variable

Difference Table

___ drugs have slightly greater risk for immunogenicity

biologic

Naming biologics

core name +unique 4 letter suffix

Immunogenicity

reaction of body's immune system to foreign substance

Biosimilar

close copies (but not identical) of biologic drugs produced by different manufacturers

Drug Classification Categories

-Chem Properties/Structure

-Mechanism of action

-Disease or condition

-Abuse potential

Schedule I Controlled substances

1. Highest abuse potential

2. no medical use

3. not prescribable

Schedule II Controlled substances

1. high abuse potential

2. with medical use

3. no refills allowed

Schedule III Controlled substances

1. Moderate abuse potential

2. medical use

3. < 5 refills per 6 mo

Schedule IV Controlled substances

1. low abuse potential

2. medical use

3. < 5 refills per 6 mo

Schedule V Controlled Substances

1. lowest abuse potential

2. with medical use

3. minimal prescribing restrictions

Cannabis is considered a schedule ___ controlled substance federally

I (1)

Orphan drug

drug for dx or Tx of a rare dz: effecting <200,000 persons in the US.

-lol (generic name stem)

beta adrenergic receptor blocker

-osin (generic name stem)

alpha adrenergic receptor blocker (cataract implications)

-vir (generic name stem)

anti-viral

-barb (generic name stem)

barbituric acid derivatives

-tinib (generic name stem)

tyrosine kinase (TYK) inhibitor

-citinib (generic name stem)

Janus kinase family of TYK inhibitors

excipients

inactive ingredients in drugs. examples: preservatives, lubricants, buffers, and coatings.