cram exam 2 pda i

What are the six current approaches to discovering new drugs / leads?

1. Screening for Biologic Activity

2. Chemical Modification of a Known Molecule

3. Rational Drug Design

4. Biotechnology and Recombinant DNA Techniques

5. New Drug Target

6. Combinations of Known Drugs to Obtain Additive / Synergistics Effects OR Repurposing of a Known Drug for New Therapeutic Use

What are the two current methods for selecting compounds for further development?

1. Compound-Based Approach

2. Target-Based Approach

What are the six stages of new drug development in chronological order?

1. Investigational New Drug (IND)

2. Phase 1 Clinical Trials

3. Phase 2 Clinical Trials

4. Phase 3 Clinical Trials

5. New Drug Application (NDA)

6. Phase 4 Post-Market Surveillance

What is the purpose for each of the six stages of the new drug development process?

1. INVESTIGATIONAL NEW DRUG (IND)

- Provide information from Pre-Clinical Trials to FDA to allow for determination if clinical trial authorization is given

2. PHASE 1 CLINICAL TRIALS

- Determine SAFETY, evaluate PK of drug (ADME) and max tolerated dose

3. PHASE 2 CLINICAL TRIALS

- Determine EFFICACY and any side effects in patients; helps FDA decide if trials continue

4. PHASE 3 CLINICAL TRIALS

- Confirm EFFICACY and optimize DOSING; evaluation of Double-Blind study results, Side Effects, and PK of drug further; helps FDA decide if trials continue

5. NEW DRUG APPLICATION (NDA)

- Includes info related to drug, including (i) manufacturing, (ii) stability and bioavailability, (iii) methods of analysis of EACH dosage form), (iv) packaging and labeling, and (v) any new toxicology data since IND

- IF APPROVED, goes out to market

6. PHASE 4 POST-MARKET SURVEILLANCE

- Part of SAFETY-FIRST INITIATIVE by FDA

- Helps determine if any previously unrecognized adverse effects have occurred

What is the timeline for each of the six stages of the new drug development process?

1. INVESTIGATIONAL NEW DRUG (IND)

- Evaluation and decision within 30 days

2. PHASE 1 CLINICAL TRIALS

- Around 1 year

3. PHASE 2 CLINICAL TRIALS

- Up to 2 years

4. PHASE 3 CLINICAL TRIALS

- Up to 4 years

5. NEW DRUG APPLICATION (NDA)

- Years 8-9 usually

6. PHASE 4 POST-MARKET SURVEILLANCE

- After approval, surveillance continues; patent lasts for 20 years after initial NDA

What three types of compounds are used for developing a new drug product using a Compound-Based Approach?

Give examples of each type.

1. Naturally Occurring Products

- Ex. Digitoxin from Digitalis purpurea

2. Purely Synthetic Drugs

- Ex. Hycamptin from Camptothecin

3. Drug Metabolites

- Ex. metabolite Fexofenadine from Terfenadine

What program was responsible for aiding in the development of Hycamptin?

DRP's RAID Program

What three methods are part of the Target-Based Approach in developing new drug products?

What do they focus on?

1. Systematic Method to Identifying Targets

- Focuses on mechanisms of diseases and life processes of pathogens

2. Screening Method

- Focuses on combinatorial chemistry and high throughput screening (quick conducting of pharmacological tests)

3. Computer Aided Drug Design (CADD)

- Focuses on using computational simulations to predict drug-target interactions

Give examples of how a hypothesis is created related to the target found by Target-Based Approaches to discovering drug targets.

Development of Protease Inhibitors for Treatment of HIV

Beta-Adrenergic Antagonists for Hypertension

Beta-Adrenergic Agonists for Asthma

What is Combinatorial Chemistry?

Screening method for discovering new drug targets based on looking at the receptor and picking out building blocks for 'key' ligand species

What technology was used to screen for a novel TGF-Beta1 Receptor Kinase Inhibitor?

CADD

What two types of studies are used to screen the activity of chosen leads for drug target discovery?

Describe each type.

1. IN VITRO STUDIES

- Cell Membranes

- More Complicated Cell-Based Systems

- High potential for both false positive and false negative because of FUNCTIONAL SELECTIVITY

2. IN VIVO STUDIES

- Once activity is established at the molecular level, the drug will be tested for its activity in the WHOLE animal

What are the six main characteristics of good therapeutic agents?

What do we look at for all six?

1. Efficacy

2. Selective in Action / Affinity

3. Delivery to Site of Action

4. Good PK (ADME)

5. No Side Effects in ALL Patients (Race / Genetic Polymorphisms)

6. Good Physicochemical Properties (Easy to Formulate and Administer)

We look at the BENEFITS TO RISKS RATIO for all six before deciding on pursuing an agent

What do we look at during Pre-Clinical Studies for drug development?

Large Scale Synthesis and Physicochemical Properties

Stability and Shelf-Life

ADME (PK Properties)

Degradation Products

Formulation(s)

Toxicity Studies in Two Animal Models

- Incl. acute, chronic, and single overdose

- No longer require animal tests after 2022 FDA Rule(????)

What marks the beginning of the Clinical Testing section of drug development?

Approval of the Investigational New Drug (IND)

How long does approval of the IND take?

Who is responsible for approving it?

FDA's Center for Drug Evaluation (CDER) looks at the IND and gives a decision on whether it is approved or not WITHIN 30 days

What is the main purpose of Phase 1 Clinical Trials?

How long does it typically last?

How many subjects are included?

Main purpose is to determine SAFETY via evaluation of (i) max tolerated dose and (ii) PK properties of ADME

Typically lasts ~1 year

Includes 20-100 HEALTHY volunteers between the ages 18-65 years old

What is the main purpose of Phase 2 Clinical Trials?

How long does it typically last?

How many subjects are included?

Main purpose is to determine EFFICACY in patients via evaluation of (i) effect in patients through single blinded studies and (ii) side effects

- Helps FDA decide whether trials can continue

Typically lasts up to 2 years

Includes 100-200 patients WITH the disease

What is the main purpose of Phase 3 Clinical Trials?

How long does it typically last?

How many subjects are included?

Main purpose is to confirm EFFICACY and OPTIMIZE DOSING via (i) evaluation of double-blinded study results, (ii) side effects, and (iii) PK properties of ADME

- Helps FDA decide whether trials can continue

Typically lasts up to 4 years

Includes 1,000-6,000 patients WITH the disease in MULTIPLE clinical sites

What is the main purpose of New Drug Application?

How long does it typically take to be approved, if it is?

Main purpose is to present certain findings from Pre-Clinical Trials in an effort to gain approval for market distribution by the FDA

- Manufacturing Specifics

- Stability and Bioavailability

- Methods of Analysis for Each of the Dosage Forms

- Packaging and Labeling

- Any New Toxicology Data since IND

Typical approval occurs during year 8 to 9 of the whole process

What is the main purpose of Phase 4 Post-Marketing Surveillance?

How long does it typically last?

What is this phase a specific part of?

Main purpose is to determine is any previously unrecognized adverse effects have occurred

Continues as long as the product is on the market, even after the initial patent expires 20 years after NDA (when generic becomes available)

Part of the SAFETY-FIRST INITIATIVE by the FDA

What specific information is included on a New Drug Application (NDA) to the FDA during drug development?

Manufacturing Specifics

Stability and Bioavailability Data

Methods of Analysis of Each of the Dosage Forms

Packaging and Labeling for Physicians and Consumers

Any New Toxicology Data since IND

From 5,000-10,000 compounds, how many compounds typically make it to the Drug Discovery Phase?

Pre-Clinical Studies Phase?

Clinical Trials Phase?

Regulatory Approval Phase?

In essence, how many drugs make it to the final phase of drug discovery to be distributed to the market?

DRUG DISCOVERY - (starting amount) 5,000 to 10,000 compounds

PRE-CLINICAL STUDIES - 250 compounds

CLINICAL TRIALS - 5 compounds

REGULATORY APPROVAL - 1 new drug

1 in 5,000/10,000 drug compounds actually make it to the market

What are the four FDA Drug Review Categories / Designations?

What do each of them designate?

1. FAST TRACK - designed to facilitate the development and expedite review of drugs to TREAT SERIOUS CONDITIONS AND FILL AN UNMET MEDICAL NEED

2. BREAKTHROUGH THERAPY - designed to expedite the development and review of drugs which may demonstrate SUBSTANTIAL IMPROVEMENT OVER AVAILABLE THERAPY

3. ACCELERATED APPROVAL - allow drugs for SERIOUS CONDITIONS that FILLED AN UNMET NEED to be approved based on a SURROGATE ENDPOINT

4. PRIORITY REVIEW - FDA's goal is to take action on an application within 6 months

What are Fast Track designated drugs eligible for?

More frequent meetings and communication with the FDA

Eligibility for Accelerated Approval and Priority Review designations

Rolling Review

- drug company can submit completed sections of its BLA or NDA for review, rather than waiting until every section of the NDA is completed before the entire application can be reviewed

When would a drug receive Breakthrough Therapy designation?

Give an example case.

When it demonstrates an effect on a SURROGATE ENDPOINT or intermediate clinical endpoint considered reasonably likely to predict a clinical benefit

Ex. Increase in Bone Mass vs. Waiting to Determine Decrease in Incidence of Fractures

What are Breakthrough Therapy designated drugs eligible for?

All Fast Track designation features

Intensive guidance on an efficient drug development program, beginning as early as Phase 1

Organizational commitment involving senior managers

What does the Orphan Drug designation make a drug qualify for?

Tax credits for qualified clinical trials

Exemption from user fees

Potential seven years of market exclusivity after approval

What is the Orphan Drug Act?

Law which incentivized drug companies to put more

resources toward the research, development, and

distribution of therapeutics for people with rare diseases,

who until then had been 'orphaned' by the medical and

scientific community

What is included in the review process used by the FDA's Office of Generic Drugs (OGD) for determining availability of generic drugs?

Management of the regulatory process to facilitate drug approvals

Establishing science initiatives to research generic drugs

Publishing data and reports on generic drug development and review

Offering educational materials and information

What must the FDA's Office of Generic Drugs (OGD) ensure regarding generic drugs?

Must ensure they:

- Contain the same API / key ingredient

- Have the same strength

- Use the same dosage form

- Use the same route of administration

What is an Abbreviated New Drug Application (ANDA)?

Generic drug application that is generally not required to include Pre-Clinical and Clinical data to establish safety and effectiveness

Purpose is to scientifically demonstrate that the product performs in the same manner as the innovator drug (BIOEQUIVALENCE)

What is the outermost layer of the cell?

Cell / Plasma Membrane

What are the four major functions of the Plasma Membrane?

1. STRUCTURE - holds together the aqueous contents of the cell

2. BARRIER - separates cellular contents from the external fluid

3. SENSITIVITY - responds to the environment

4. REGULATION - controls transport of substances in and out of the cell

What are the primary constituents of the Cell Membrane?

Lipids

Proteins

Carbohydrates

What is formed when Lipids link covalently with Proteins?

Carbohydrates?

Lipids + Proteins --> Lipoproteins

Lipids + Carbohydrates --> Glycolipids

What determines the folding structure of a protein?

It's surrounding environment

What is the characteristic equation of Carbohydrates?

1:2:1, of Carbon (C), Hydrogen (H), and Oxygen (O)

Why are Glycolipids and Glycoproteins important for the structure of the Plasma Membrane?

When embedded in the cell membrane, they cover the surface with specific Oligosaccharide structures that are often crucial for CELL FUNCTION

What is the Lipid Bilayer?

What model is used to describe its structure best?

Explain this model.

Basic structural unit of the cell membrane, which has many proteins embedded in it

Described best by the FLUID MOSAIC MODEL, which states that the cell membrane (lipid bilayer) acts as a FLUID STRUCTURE in which constituent molecules are free to diffuse in the plane of the membrane

What are the primary lipids that compose biological membranes?

Describe the structure of these lipids.

Phospholipids

Consists of:

- Glycerol Backbone

- Hydroxyl Group linked to Phosphate Group

- Two other Hydroxyls are esterified to FA Carboxyl Groups (Saturated or Unsaturated)

- Other Phosphate end binds to Alcohol

What types of Alcohols can be bound to the Phosphate Group of a Phospholipid?

What significance does the Alcohol serve in a Phospholipid?

Most commonly a Nitrogen-Containing Alcohol, like Choline

Can also be:

- Ethanolamine

- Serine

- Threonine

- Inositol

Alcohol gives the Phospholipid its name (ex. Phosphatidylcholine)

What are the two types of cellular proteins present in the Lipid Bilayer?

What do each type do in regards to functioning in the Bilayer?

Give examples of each type.

1. SOLUBLE PROTEINS - found in aqueous environments; fold with Hydrophilic exteriors and Hydrophobic interiors

- Ex. Plasma Proteins, Enzymes

2. MEMBRANE PROTEINS - near the Hydrophobic region; folded so that a large number of Hydrophobic AAs are either (a) anchored into the bilayer or (b) extended through the bilayer

- Ex. Various Integral and Transmembrane Proteins (Markers, Receptors, and Transporters)

How are Membrane Proteins named?

Named based on their function

What is the main function of Marker Proteins?

What general type of proteins do they fall under?

Help identify cells to each other

Considered Membrane Proteins

What is the main function of Receptor Proteins?

What general type of proteins do they fall under?

Help transmit signals from the exterior to the interior of the cell

Considered Membrane Proteins

What is the main function of Transporter Proteins?

What general type of proteins do they fall under?

Regulate transport of materials in and out of cells

Considered Membrane Proteins

What two subtypes of Proteins are considered Transport Proteins?

What are their functions?

1. CHANNEL PROTEINS - create a channel or pore through which small, hydrophilic molecules can pass and are SPECIFIC for solute / ion types (sometimes GATED)

2. CARRIER PROTEINS - substrates bind to these proteins and they transport the substrate in or out of the cell

What are the three main mechanisms of transport across SEMIPERMEABLE Cell Membranes?

Describe what types of molecules are moved with each mechanism.

Which mechanism is most common for drug transport?

1. PASSIVE DIFFUSION - transport of small molecules solutes (MAIN MECHANISM FOR DRUGS)

2. CARRIER-MEDIATED TRANSPORT - transport of both small and large molecules of appropriate properties

3. ENDOCYTOSIS / EXOCYTOSIS - transport of macromolecules, such as proteins and certain particles (ex. Viruses, Bacteria)

What is Passive Diffusion?

What are the energy requirements for this type of Transport?

Movement of solutes from HIGHER to LOWER concentration until equilibrium is reached

Is NOT energy dependent and proceeds so long as there is a concentration gradient

How do solutes cross the membrane during Passive Diffusion?

Two ways, including:

- 1. BY DIFFUSION, if solute is nonpolar / hydrophobic

- 2. THROUGH PORES, if solute is polar / hydrophilic (transmembrane channel proteins)

What mechanism is responsible for the majority of drug transport across bilayers?

Passive Diffusion

What equation is used to calculate the rate of Passive Diffusion across a Lipid Bilayer?

Give the equation and what each variable means.

Fick's Law

dC / dt = - [P x A x D x (C1 - C2)] / h

where:

P - partition coefficient

A - surface area

D - diffusion coefficient

h - thickness

C1 - extracellular conc. of UNionized solute

C2 - intracellular conc. of UNionized solute

NEGATIVE SIGN DENOTES DECREASE IN DONOR SIDE CONC. WITH TIME

What is the relationship between Lipophilicity and Fick's Law?

If a molecule / solute is:

- More Lipophilic (large P, partition coefficient)

- Has a greater conc. gradient (C1 - C2)

- Crosses a thinner membrane (lower h)

Then, transport rate will be HIGH

What is the permeability like across lipid bilayers for solutes that ionize?

What does this mean for the conc. gradient?

Bilayer is permeable ONLY to the UNIONIZED form

This means only the conc. gradient of the UNIONIZED form matters for driving force (HA, B for Acid-Base)

What equation allows us to calculate the ratio between Basic and Acidic forms of a drug?

What needs to be known in order to use this?

Henderson-Hasselbalch Equation

Need to know (i) pKa of the drug and (ii) pH of the solution

When is equilibrium reached, in regards to unionized solute concentrations across the lipid bilayer?

How does this change the ionized solute concentrations?

Equilibrium is reached only when the UNIONIZED SOLUTE CONC. is EQUAL on both sides

Conc. of ionized solute will be HIGHER on side where pH favors greater ionization

How does conc. of ionized solute change across lipid bilayers?

How does this change the TOTAL solute concentration?

Conc. of ionized solute is higher on side with pH that has greater ionization potential

This causes TOTAL solute conc. to move to side with more ionization, causing it to become TRAPPED (ION TRAPPING) on the side of greater ionization

What is Carrier-Mediated Transport?

Polar solutes cross the cell membrane by hitching a ride on a Transport or Carrier protein, called a Transporter

What are Transporters?

Integral membrane proteins with one or more active sites for its POLAR Substrate

What family of transporters are responsible for transporting Glucose?

GLUT Transporters

Do Transporter substrates need to be polar or nonpolar?

Do NOT need to be Lipophilic (hydrophobic)

What are Transporters called that only transport one molecule at a time?

Are all transporters like this?

Uniporters

No, not all transporters are Uniporters; many are NON-SELECTIVE and transport DIVERSE SUBSTRATES

How does genetic variability in Transporters influence us, in regards to drug action?

Influences drug uptake and action in individuals (diversify)

What are the two major types of Carrier-Mediated Transport?

Describe each type.

Do they require energy?

1. FACILITATED DIFFUSION - carrier-mediated process that occurs only when there is a conc. gradient between donor and receiver

- Does NOT require an energy source (reliant on gradient)

- Ex. GLUT1 for Glucose

2. ACTIVE TRANSPORT - carrier-mediated process that occurs AGAINST a conc. gradient

- REQUIRES an energy source (hence the name)

What are Antiporters?

Transporters that can transport one molecule in one direction adn another in the opposite direction

What are Symporters?

Transporters that simultaneously transport two solutes in the SAME direction

What are some examples of drugs that utilize Active Transport?

5-Fluorouracil

Some Cardiac Glycosides (across Intestinal membrane)

What is the main function of Efflux Pumps / Transporters?

What do they require to function?

What do they serve as a barrier for?

Main function is to REMOVE TOXIC SOLUTES out of the cell

Require ATP to function

Provide a barrier to UPTAKE OF XENOBIOTICS

What is a Multidrug Resistance Transporter (MDR)?

Give two examples of MDRs.

Single Type of Transporter that can RECOGNIZE and PUMP OUT many different types of drugs to limit their effectiveness

Examples:

- P-Glycoprotein

- Multidrug Resistance Protein (MRP)

Where are Efflux Pumps / Transporters found?

Cells of the GI Tract, Liver, and Kidney

In Drug-Resistant Microorganisms

What are the two main Vesicular Transport Processes?

How do they work in response to conc. gradients?

Do they require energy?

ENDOcytosis and EXOcytosis

Can occur AGAINST a conc. gradient

REQUIRE cellular energy

What are the three primary mechanisms of Endocytosis?

Describe each mechanism.

1. RECEPTOR-MEDIATED ENDOCYTOSIS - molecules bind to receptors before being taken into the cell

2. PINOCYTOSIS - less specific mechanism; cell ingestion using a small amount of liquid from the extracellular fluid surrounding the cell

3. PHAGOCYTOSIS - cell engulfs large particles, such as Bacteria and Viruses; mainly serves as a defense mechanism

What is Exocytosis?

Vesicular transport process in which a membrane-enclosed vesicle in the cell fuses with the plasma membrane and then opens and releases its contents into the extracellular fluid

What must all drugs encounter at the site of administration?

What route of administration is the exception?

All drugs encounter an EPITHELIAL LINING at the site of administration

The exception is with INTRAVENOUS administration

What two types of transport can drugs use to cross the Epithelial Lining at the site of administration?

Describe each type.

1. TRANSCELLULAR TRANSPORT - drug or other molecules pass THROUGH the cell layer

2. PARACELLULAR TRANSPORT - drug or other molecules pass through the aqueous space BETWEEN the cells

Which type of transport across tissues is more common with drug action?

Why?

TRANScellular Transport is more common

Tight Junctions that hold cells together form tight seals that most drugs cannot penetrate, therefore they cannot utilize Paracellular transport and must go through the cells instead

What is Endothelium?

How do they compare to normal epithelial cells?

Specialized type of epithelial tissue that makes up the walls of blood vessels and lymph vessels

They are more LOOSELY packed and the gaps between them contain a loose network of proteins that act as FILTERS for larger molecules (let small molecules through)

Which pathway for drug transport across tissue is most important for transport across the Capillary Endothelium?

Why?

PARACELLULAR transport

Paracellular Transport is passive, so molecules can diffuse if they are smaller than the junction diameters despite lipophilicity status

What is the diameter range for Capillary Endothelial Junctions?

Up to what molecular weight can molecules diffuse through these junctions?

Diameter 5 - 30 nm

Up to MW of 30K can diffuse

What is the Blood-Brain Barrier (BBB)?

Specialized system of capillary endothelial cells that protects the brain from harmful substances in the bloodstream, while supplying it with nutrients

How does the BBB compare to Peripheral Capillaries?

Peripheral Capillaries - allow free exchange of small molecules and tissues

BBB - limits transport into the brain through physical (TIGHT JUNCTIONS) and metabolic (ENZYMES) barriers

How do physical barriers in the BBB affect molecular transport?

Tight Junctions in the brain force molecules to only enter or leave by Transcellular pathways

What is the rate-limiting factor in determining entry of drugs into the brain?

The Blood-Brain Barrier (BBB)

What two origins can Systemic drugs be absorbed from?

Give an example of each origin.

1. Directly from Site of Administration

- Ex. Transdermal Patches, where site of administration is the same as site of absorption

2. From Site of Administration to Different Region

- Ex. Oral Drugs, where drugs are administered orally but absorbed later in the Small Intestines

Where does most absorption occur for Oral drugs?

Small Intestines

Regardless of the site of administration for a drug, what two commons factors exist for drug absorption?

1. Drug must be dissolved in body fluids are the site of absorption for it to be absorbed

2. Dissolved drugs must cross the epithelial tissue at the absorption site, the capillary endothelium of BVs, and then enter bloodstream

What is the slowest / rate-limiting step for drug absorption?

Drug's ability to cross the epithelial membranes at an absorption site

What five factors control drug absorption?

1. Solubility of the Drug

2. Dissolution Rate

3. Drug Concentration

4. Circulation at the Site of Absorption

5. Surface Area of the Absorbing Site

Which route of systemic drug administration is the most common and considered the easiest and safest?

Oral Administration

What is the main influence on Oral drug administration and absorption?

Where does it move through?

Main influence is the pH of the stomach (1-3) and its contents (GI fluids)

Moves through the GI Tract and is absorbed in several different regions

What is the site of dissolution for Orally administered drugs?

How does this site affect the absorption of the drug?

Site of dissolution is the STOMACH

Has LITTLE ABSORPTION of weakly acidic / basic drugs due to short residence time in the stomach and limited SA

What are the three main parts of the Small Intestine?

How long is it all together?

Duodenum, Jejunum, and Ileum

6-7 meters in length

What is the main site of absorption for Orally administered drugs?

Why?

Small Intestine is main site for absorption

This is due to the enormous SA and long residence time (4-6 hours)

What components comprise the Intestinal Fluid?

Complex mix of:

- Mucus

- Acid

- Digestive Enzymes from Liver (Bile) and Pancreas (Pancreatic Juice)

What are the three main parts of the Large Intestine?

How long is it all together?

Cecum, Colon, and Rectum

1.5 meters in length

What is the main function of the Large Intestine?

Absorption of water and electrolytes from indigestible food matter

How long does undigested food spend in the Large Intestine?

30 to 40 hours

What is the main role of the bacterial contents of the Large Intestine?

Prevent growth of pathogenic bacteria and help in the production of Biotin and Vitamin K

What is the main drawback to Oral routes of administration when considering drug absorption?

Oral routes are subject to the First-Pass Hepatic Effect