intro to drug discovery, development & approval processes

What is pharmaceutics?

is the art, science, and technology of dosage form design (preparing and dispensing drugs and medicinal agents)

• technology → we need special equipments to make up dosage forms like tablets and capsules, for example

• art → we need to make sure that the medication bottle and label looking appealing so that the patient keeps up with their medication as needed

physiochemical properties are what?

stability, ionization, water/lipid solubility, hydrolysis, oxidation, racemization, etc

biological properties are what?

absorption, transport, biotransformation, etc.

dosage forms are what?

physical forms such as capsule, tablet, solution, etc.

dosage form formulation are what?

combination of different ingredients

what is a drug?

an agent intended for use in the diagnosis, mitigation, treatment, cure, or prevention of disease in humans or in other animals (Food, Drug, and Cosmetic Act, 1938)

• pure chemical

• mitigation: to reduce

• ex: acetaminophen

what are excipients?

inactive ingredients used in the preparation of dosage forms

• inactive means that they do not do anything, they have no pharmacological action

• ex: corn starch, cellulose, magnesium stearate

what is formulation?

pharmaceutical formulation, is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal (drug) product

what is a drug product?

a specific combination of an active pharmaceutical ingredient, and generally, but not necessarily other inactive ingredients

• combo of inactive and generally a drug

what is a dosage form?

drug products in the form in which they are marketed for use (tablets, capsules, solutions), with a specific combination of active ingredients and inactive components (excipients), in a particular configuration

what is a drug substance?

Active Pharmaceutical Ingredient (API): it is the material that exerts the pharmacological action. Along with other ingredients (excipients, inactives), it is subsequently used to formulate the drug product

• 99% drug, 1% impurities

what is an impurity?

an impurity is any component present in the excipient, drug substance, or drug product that is NOT:

• the desired product

• a product-related substance

• or excipient (including buffer components)

what is a prescription drug?

a human drug that is not safe for use except under the supervision of a licensed medical practitioner

what are drug standards?

• uniform standards to ensure quality

• development/publication of monographs and reference books

• organized sets of monographs/books of standards - pharmacopeias or formularies

• over 5000 quality standards - drug substances, pharmaceutical ingredients, & dosage forms

• provides best current practices, suitable tests and assay procedures

what organizations are part of drug standards?

United States Pharmacopeia (USP) and National Formulary (NF)

United States Pharmacopeia (USP)

• 1820 - 1st USP published

• Other e.g. - British Pharmacopeia, Japanese Pharmacopeia, Indian Pharmacopeia

→ public standard organization (not overseen by gov)

National Formulary (NF)

• initially developed to include drugs omitted by USP

• 1975 - merged with USP

Goal of pharmaceutical care

• optimize the patient’s health - related quality of life

• achieve positive clinical outcomes within realistic economic expenditures

• participate fully in all aspects of medication distribution & their appropriate clinical use

t or f: drug product and dosage form are the same things

f

• drug product: combo of active and inactive

• dosage form: capsules, tablets, etc

The long road to a new medicine

• about 10-15 years to develop a drug and bring it to the market

• about 1-2 billion US dollars

• drug discovery (gene or genome sequencing, target discovery, lead discovery) → animal studies (pre-clinical) → clinical tests (clinical phase I, clinical phase II, clinical phase III) → commercialization (manufacturing, distribution)

Gene or genome sequencing (drug discovery)

• building a library of gene/protein (genome/proteome) sequences to mine for information

target discovery (drug discovery)

• look for proteins or mRNA expressed (or not expressed) in a disease

  • ex: Alzheimer’s disease

• look for genes/proteins essential for infectious agent and distinct from host genes/proteins

  • ex: Covid’s spike proteins

• look for genes and gene modifications associated with a disease

• look for proteins or protein modifications associated with a disease

• find regulatory pathways required for disease process

  • ex: blood clotting (happens in steps)

THINK “DISEASE”

lead discovery (drug discovery)

discover leads (drug molecules) that affect the target gene, protein or pathway

• inhibits a protein causing the disease

  • ex: sickle cell anemia

• activates a required protein

• inhibits the expression of a protein/pathway that causes the disease

• activates the expression of required protein/pathway

• stimulates protein modifications or cellular location

THINK “FINDING DRUGS”

what is the point of drug discovery?

1. gene/genome sequencing - understand the disease

2. target discovery - identify the root cause of the disease, find the target(s)

3. find drug molecules that influence/modulate the target

which of the following is the most accurate example of target discovery?

a) inhibition of a required protein

b) looking for proteins or protein modifications associated with a disease

c) activation of a required protein

d) stimulation of a protein modification

b

• think “DISEASE”

which of the following is an example of dosage form?

a) API

b) drug substance

c) solution

d) corn starch

c

• physical forms of the drug (tablets, capsules, solutions, etc.)

the USP and NF are examples of:

a) gene editing tools

b) clinical trial designs

c) drug discovery databases

d) drug standard references

d

• standard setting organization (tells us quality of products, dosage form, etc.)

involvement of genetic mutation of hemoglobin protein in sickle cell anemia is an example of:

a) target discovery

b) lead discovery

c) gene sequencing

d) preclinical trials

a

• target discovery is trying to find the root cause of the disease. lead discovery is trying to look for drug molecules that can cure that disease.

• this question is telling us that there is something wrong with this protein (hemoglobin) in the disease sickle cell anemia

• think “DISEASE”

antisense oligonucleotides specific to hemoglobin protein causes reversal of sickle cell anemia. this is an example of:

a) target discovery

b) preclinical trials

c) lead discovery

d) gene sequencing

c

• there was a reversal of sickle cell anemia, meaning that there was a drug that reversed it

• when thinking “lead” think “drug”

what are the drug discovery methods? (lead discovery)

1. screening natural compound collections

2. screening corporate compound collections

3. In silico screen ing (Autodock)

4. rational drug design

5. combinatorial chemistry

Screening natural compound collections

look for natural resources (plants, berries, bacteria, virus, etc) so you can extract from them and see if they give any relief from pain or injury

→ very slow and tedious process

How to test for screening?

• random screening (in lab setting using wells)

• testing compounds of natural origin for biologic activity

• uses in vitro cell culture models or enzyme systems for testing

screening corporate compound collections

→ relatively fast process

→ high-throughput screening

→ about 15,000 compounds per week

→ 10-20 biological assays

In silico screening (autodock)

• biological experiments conducted on a computer

• 3D structure of a target (receptor, enzymes, protein, etc.) used for screening

• In silico tools stimulate binding of candidate molecules to the target

• estimate the likelihood of successful interaction

• DISADVANTAGE: screen thousands but you don’t know if the binding efficiency is good or not

rational drug design

• requires the knowledge of 3D structures of the target

  • specifically the active site

• computer graphics used to design a drug with a specific structure that binds to the active site

  • predicts one structure at a time (computer)

which of the following accurately differentiates In silico screening vs. Rational drug design?

a) biological experiments conducted on a computer

b) estimate the likelihood of successful interaction

c) 3D structure of the target is required

d) random screening of several thousand molecules

d

• both use computers

• both tell binding efficiency (both generate a potential structure that might bind)

• both use 3D

• random screening of several thousand molecules is for In silico

combinatorial chemistry

• preparation of a large number of different compounds at the same time

• high throughput-screening provides the most promising substances

what is lead optimization?

structure modifications to improve ADMET properties

• another step of lead discovery

ADMET: ideal properties of drugs

Absorption - passes GI tract into blood stream

Distribution - gets to target tissue

Metabolism - not readily metabolized

Excretion - not readily secreted

Toxicity - not toxic to other cells or tissues

Who is/are responsible for drug approval?

• a federal agency established in 1906 known as Food and Drugs Administration (FDA)

• part of the Public Health Service (PHS), funded in part by Congress through the department of Health and Human Services (HHS)

• separate centers within the FDA regulate drugs, biologicals, devices, and food

  • Center for Drug Evaluation and Research (CDER)

  • Center for Biologics Evaluation and Research (CBER)

Center for Drug Evaluation and Research (CDER)

approves small-molecule drugs

• determines over-the-counter vs. prescription status

Center for Biologics Evaluation and Research (CBER)

approves biologics drugs

How to gain drug approval?

The drug will need to go through the FDA before it may be legally introduced in the interstate commerce. They have to make sure that it both safe and effective for its purposed use.

pre-clinical (animal studies)

1. biologic tests for toxicity and efficacy of therapy (rats, mice, monkeys)

   1. pharmacology

   2. drug metabolism

   3. toxicology

2. preformulation studies

3. formulation studies

when giving to animals, you should be able to gather what the drug is meant for (pain reduction) and the dosage form

INVESTIGATIONAL NEW DRUG (IND) is at the end of pre-clinical

investigational new drug (IND) [animal studies]

• submit IND application

• FDA reviews all preclinical testing and plans for clinical testing to determine if the drug is safe to move to human trials

• FDA response time: 30 days

  • must get back to you within thirty days; if not, you may proceed to the next step

clinical trials phase I (clinical tests)

• 20-100 healthy volunteers take drug for about one month

checks for:

1. low initial dose

2. absorption and metabolism

3. effects on organs and tissue

4. side effects as dosage is increased

MAIN PURPOSE: assessing safety

• approx. 70% of drugs may move to next stage

clinical trials phase II (clinical tests)

• 100-1000 health-impaired patients

checks for:

1. dose range (low, medium, high)

2. effectiveness in treating disease

3. short-term side effects

MAIN PURPOSE: assessing effectiveness

• approx. 33% of drugs may move to next stage

• 2 groups

  • control group is there to compare with the treatment group. there may be a similar drug on the market already and we are trying to see if the new one is better or not

clinical trials phase III (clinical tests)

• 300-3000 health-impaired patients (everywhere around world)

checks for:

1. benefit/risk relationship of drug

2. less common and longer term side effects

3. labeling information (add to label if another thing is discovered to be helped with)

• approx. 25-30% of drugs move to the next stage

New Drug Application (NDA) [after clinical trials phase III)

• the sponsor may file NDA, if clinical trials demonstrate the drug safety, and therapeutic effectiveness

• purpose is to gain permission to market the drug product in the US

• FDA must respond within 180 days of receipt of an application. this is known as review clock

  • review clock can be extended

phase IV - post marketing surveillance

• may contribute to the understanding of the drug’s mechanism or scope of action

• may indicate possible new therapeutic uses for the drug, and/or may demonstrate the need for additional dosage strengths, dosage forms, or routes of administration

• these studies may also reveal additional side effects, serious and unexpected adverse effects, and/or drug interactions

• practicing pharmacists and other health care professionals participate in adverse drug experience reporting through the FDA’s MedWatch program, using forms

what is the FDA’s primary role in drug approval?

a) manufacturing regulation

b) drug safety and effectiveness evaluation

c) marketing authorization for cosmetics

d) patent filing for new drugs

b

• safety and effectiveness = FDA

• best to be first and after approval of IND, you have 20 years to put it into the market (ways to make money)

an IND is typically filed _______________

a) before preclinical trials

b) after preclinical trials

c) after phase I clinical trials

d) after phase III clinical trials

b

• after all the animal studies are done

reasons for failures in new drug development

• efficacy 46%

• animal toxicity 17%

• adverse effects 16%

• pharmacokinetics 7%

• commercial 7%

• miscellaneous 7%