BPS 301 EXAM1/EXAM2 COMBO

What does “Cp” mean?

Plasma concentration of a drug. Pharmacokinetics

What does “CSA” mean?

Concentration of a drug at the site of action. Pharmacodynamics

Why are PK-PD relationships graphed using a log conversion

Compress X axis, show larger dosage range

What measures absorption?

Bioavailability

Where is the primary site of drug metabolism?

The liver (hepatic elimination)

Where is the primary site of drug excretion?

The kidneys (renal excretion)

Why is plasma concentration used to measure drug content vs whole blood?

More consistent representation of drug concentration

What is onset time?

The time required for the drug to reach the minimum effective concentration after administration

What does “intensity” refer to in this course?

Proportional to the number of drug receptors occupied, which is reflected in the observation that higher plasma drug concentrations produce a greater pharmacologic response, up to a maximum

What is the duration of drug action?

The difference between the onset time and the time for the drug to decline back to the minimum effective concentration

What is drug exposure? What is used to measure drug exposure?

Drug exposure is the dose and various measures of drug concentrations in the plasma/other biological fluids

Measured: Cmax, Cmin, Css, AUC

AUC most common measurement

What is represented by the letter “F”?

Bioavailability 

What is a trans-cellular passageway?

A passage that goes through the cell’s lipid bilayer. Lipid junction

What is a paracellular passageway?

A passage that goes through the junction between the cells. Aqueous junction

What is diffusion?

The general movement of molecules from high concentration → low concentration

• No barrier

• No energy needed

What is permeability?

Movement through a barrier/membrane which slows or prevents diffusion

• No energy needed

• Is a RATE

• Controlled by physical properties of membrane + molecule moving through it

What happens during passive diffusion across a membrane?

• Free unbound drugs

• High concentration → Low concentration

• Unbound high concentration = C1

• Unbound low concentration = C2

• Solid drug cannot pass through membrane, cannot diffuse

• Protein-bound drugs cannot diffuse

What factors affect the rate of passage?

• Concentration gradient (C1-C2)

• Permeability of drug through a membrane (P)

  • Lipophilicity, P, logP

  • pH, pKa, dissociation, ionization (D), logD

• Surface area of the membrane (SA)

Are paracellular junctions hydrophilic or hydrophobic?

Hydrophilic

What is the partition coefficient (P)? Why is it important?

What it is: Guide to lipid vs aqueous solubility of molecule

Why is it important: Lipophilicity affects permeability, impacts dissolution and ADME

How is partition coefficient assessed?

Drug is added to a container w n-octanol (oil) and water

• Container is shaken, drug concentration in n-octanol and water is measured

• Ratio of drug concentration = P

P = C_octanol/C_water

What does a large logP value indicate?

The drug is lipophilic

What does a small logP value indicate?

The drug is hydrophilic/polar

Will a drug with a higher logP or a lower logP value be better absorbed? Why?

Higher logP value drugs will be better absorbed. Cell membrane is lipophilic, “like-dissolves-like”

is logP pH dependent?

No. logP only applies to neutral compounds

What is the effect of ionization on lipophilicity?

The ionized form of a drug is hydrophilic, degree of ionization impacts effective lipophilicity

Are acids more ionized above or below their pKa?

Above

Are bases more ionized above or below their pKa?

Below

Can the unionized form or the ionized form pass biological membranes?

Only the unionized form

What pH will promote diffusion of weak acids?

Low pH

logD value will X as pH values Y

What pH will promote diffusion of weak bases?

High pH

logD value will X as pH values Y

What factors determine a drug’s ability to diffuse across a biological membrane?

• pKa of the drug

• pH at the absorption site

• Drug partition characteristics (LogP, LogD)

How are molecules transported through membranes during paracellular passive diffusion?

Pores or junctions

How are molecules transported through membranes during transcellular passive diffusion?

Directly through the membrane

How are molecules transported through membranes during transport mediated processes

Proteins

What are some membrane properties that control permeability?

1. Membrane type

2. Surface area

3. Thickness of membrane (transcellular)

4. Perfusion on other side of membrane (transcellular)

5. Size of junction (paracellular)

What drug factors control permeability?

1. Lipophilicity

2. Size of molecule

3. Polarity

What is more efficient: paracellular passive diffusion, or transcellular diffusion? Why?

Transcellular

• Larger surface area

• Faster and isn’t limited by tightness of junctions

What is paracellular permeability dependent on?

• Size of junction pores between cells

• Size/additional properties of the molecule

What compounds use the paracellular method of diffusion?

Polar compounds that CANNOT pass through by transcellular diffusion or cannot be carried by protein transporters

Last resort

Why are positively charged molecules transported more easily than negatively charged molecules in paracellular diffusion?

Complex of junctions have a mainly net negative charge

What types of drugs are absorbed via paracellular transport?

Small (< 250 Da) and hydrophilic (logP < 0)

List examples of “tight” cell junctions

• Skin

• BBB

• Retina

• Testes

• Placenta

• GI tract has medium pore size

List examples of “loose” junctions

• Nasal mucosa

• Renal glomerulus

• Capillarity epithelium of most tissues

Is it easier for compounds to pass paracellularly if the junctions are tight or if they are loose?

Loose

What parts of the body have no paracellular permeability. Why?

• Hepatocyte

• Renal tubule

• BBB

Junctions are too tight

What are “transporters”?

Proteins on cell membranes that facilitate passage of molecules in/out of cells

• Reversibly binds (affinity + selectivity)

• Releases chemical at other side of the membrane

What are characteristics of transporter systems?

• Highly selective

• Fixed number

  • Binding sites can become saturated at high drug concentrations

• Enables competition

• Under genetic control

What are the two main types of transporters?

Uptake

• Takes drugs INTO the cell

Efflux

• Takes drugs OUT of the cell

How do uptake transporters transport drug molecules?

• Along concentration gradient

• Not energy dependent

• Bidirectional

How do efflux transporters transport drug molecules?

• Unidirectional

• Energy dependent

What are the key intestinal uptake transporters?

• PEPT1

• OCT3

What are the key intestinal efflux transporters?

• Pgp

• MRP2

• BCRP

How is permeability assessed?

• PAMPA (Parallel artificial membrane permeability assay)

• In silico tools

• MDCK-LE (canine kidney cells)

• Caco-2 (colon cancer cell line)

What is PAMPA?

Parallel Artificial Membrane Permeability Assay

In vitro model of passive, transcellular diffusion

How can you increase passive permeability?

• Optimize lipophilicity

• Reduce hydrogen bonds

  • Intra-molecular hydrogen bonds instead

• Reduce polarity

• Reduce MW

• Reduce rotatable bonds

• Remove carboxylic acid for brain penetration

• Use a prodrug

What steps are taken for a drug to enter systemic circulation?

1. Consumption

2. Disintegration / dissolution

3. Membrane penetration / diffusion

4. Uptake and efflux transport

5. Metabolism in the enterocyte

6. Metabolism/transport during first pass thru liver

7. Drug enters systemic circulation

What pre-clinical data is used to predict clinical absorption and clearance mechanisms?

• Chemical properties

  • solubility, pKa, logP, logD, MW, PSA (polar surface area), HBA (hydrogen bond acceptor), HBD (hydrogen bond donor)

• Peremability assays

• Transporter substrate assays

• Drug metabolism substrate assays

What does BCS stand for?

Biopharmaceutics classification system

What is BCS used for?

To judge new formulations of an approved drug and predicts rate-controlling steps of absorption

How many BCS classes are there?

4

Describe BCS class 1 drugs

High permeability, high solubility

• Oral absorption is not solubility limited. Drug absorption unlikely to be dependent on drug dissolution/GI transit time

• In vivo bioavailability and bioequivalence studies NOT NEEDED for new IR formulations

Describe BCS class 3 drugs

Low permeability, high solubility

• Oral absorption is NOT solubility limited. Limited by permeation.

• In vivo bioavailability and bioequivalence studies are not needed for new IR drug formulations

What BCS drug classes do NOT need bioavailability and bioequivalence studies for new immediate release (IR) formulations?

• Class 1

• Class 3

Both have high solubility

How is permeability measured?

• logP

• Partition coefficent

• Distribution coefficent

• LogD

  • % ionization at specific pH (pKa)

    • (+/-) prefers aqueous layer

    • Neutral prefers lipid layer

• Experimental measures

  • PAMPA

  • Papp (MDCK cell line)

  • CLpassive

In BCS, what are biowaivers based on?

The extent of intestinal permeability (absorption)

• Typically correlates w intestinal permeability rate

What does BDDCS stand for?

Biopharmaceutics Drug Disposition Classification System

How does BDDCS differ from BCS?

BCS considers intestinal permeability EXTENT

BDDCS considers intestinal permeability RATE (metabolism)

What drug classes are metabolized before elimination? Why?

• Class 1

• Class 2

High intestinal permeability

What drugs are eliminated into the urine/bile and remain unchanged?

• Class 3

• Class 4

Low intestinal permeability

What does BDDCS predict?

Major route of elimination

• Based on intestinal permeability rate and solubility

What does ECCS stand for?

Extended clearance classification system

What does ECCS predict?

The predominant clearance organ and mechanism

• further subclassifies BDDCS

How are ECCS classes categorized?

Charge (neutral, anionic, cationic) and molecular weight (large, small)

What are the ECCS classes?

• 1A

• 1B

• 2

• 3A

• 3B

• 4

Which ECCS classes are cleared by metabolism?

• 1A

• 2

Which ECCS classes are eliminated as metabolites?

• 1A

• 1B

• 2

Which ECCS classes are eliminated as parent drug in urine?

• 3A

• 3B (also bile)

• 4

What ECCS class has extensive metabolism, is highly permeable, and is an acid/zwit when ionized?

Class 1

• 1A if small MW

• 1B if large MW

What are the differences between class 1A and class 1B (ECCS)?

Drugs in the 1A class have a low MW, are absorbed by diffusion, and are cleared by metabolism/excreted as metabolites

Drugs in the 1B class have a high MW, are absorbed by hepatic uptake (OATP transporters), cleared by metabolism/excreted as metabolites

What are the hepatic uptake transproters

OATPs

What are the renal secretory transporters?

OATs

What ECCS class has extensive metabolism, is highly permeable, and is a base/neutral when ionized?

Class 2

How are class 2 ECCS drugs:

• absorbed?

• cleared?

• excreted?

Absorbed= diffusion

cleared= metabolism

excreted= metabolites

What ECCS class has poor metabolism, low permeability, and is an acid/zwit when ionized?

Class 3

• 3A

• 3B

What are the differences between class 3A and class 3B drugs?

3A have small molecular weight and is renally cleared; excreted in urine as parent/unchanged drug

3B have large MW and is cleared by hepatic uptake (bile, unchanged) OR renal clearance (urine, unchanged)

What are the intestinal efflux transporters

P-gp and BCRP

What ECCS class has poor metabolism, low permeability, and is a base/neutral when ionized?

Class 4

How are class 4 ECCS drugs:

• absorbed?

• cleared?

• excreted?

Absorbed by hepatic uptake

Cleared renally

• Active renal secretion

• Efflux transport

Excreted in urine, unchanged

How many phases of clinical trials are there?

4

What is the main purpose of phase 1 clinical trials? How large are phase 1 trials? How long do phase 1 trials last?

Safety

• Test new drugs for first time in small group

• Evaluate safe dosage range, ID side effects

• Aprox. 20-80 healthy volunteers

• Lasts several months

What is the main purpose of phase 2 clinical trials? How large are these trials? How long do phase 2 trials last?

Safety and dosing

• Further evaluate safety

• Monitor side effects/adverse effects

• Assess efficacy

• Aprox. 100-300 subjects

  • Participants with disease included

• Lasts several months

What is the main purpose of phase 3 clinical trials? How large are these trials? How long do phase 3 trials last?

Safety and efficacy

• Confirm effectiveness

• Monitor safety

• Distributed to different countries and regions to test larger population

  • Several hundred to several thousand

• Lasts several years

What is the main purpose of phase 4 clinical trials?

Post-marketing safety and efficacy

• Continue to gather info on drug’s effect in various populations

• Gather info on any side effects associated with long-term use

What are the requirements for a generic drug?

• Same active ingredients

• Same labeled strength

• Same dosage form

• Same administration

Congress passes an Act that requires the FDA to write regulations explaining how the law will be enforced. Where would the FDA put the proposed regulations for public comment?

The federal register

What are the goals of the Drug Supply Chain Security Act?

1. Enable secure tracing of product at the package level

2. Use product identifiers to verify product at the package level

3. Enable prompt response to suspect and illegitimate products when found

4. Improve efficiency of recalls

5. Establish national standards for licensure for wholesale distributors and third-party logistics providers (3PLs)

What is a biosimilar?

What is an interchangeable biologic?

What does a company need to submit if they want to market a generic drug?

Abbreviated new drug application (ANDA)