Kinetics: Lecture 12: Bioavailability And Bioequivalence; Biopharmaceutic Considerations In Drug Product Design

Front 1

What is a generic name?

Back 1

An established non-proprietary common name of active ingredient. (such as acetaminophen)

Front 2

What is a chemical name?

Back 2

Used by organic chemists and indicates structure. (ex. p-acetamidophenol or p-hydroxyacetaniline)

Front 3

What is a brand name?

Back 3

A privately owned trade name of a drug. (ex. tylenol)

Front 4

What is "bioavailability"?

Back 4

It is a reference to the rate and extent to which a drug is absorbed.

Front 5

How are F and ka related to bioavailability?

Back 5

F and ka are direct measures of bioavailability but are too variable to be useful for this purpose.

Front 6

What are some indirect measures used to determine the bioavailability of a drug?

Back 6

From and oral Cp verses t curve: The Cmax, tmax, and AUC are used (INDIRECT MEASURES).

Front 7

What is Cmax a measure of?
(in oral Cp vs. t curve)

Back 7

The rate and extent of absorption.

Front 8

What is tmax a measure of?
(in oral Cp vs. t curve)

Back 8

The rate of absorption.

Front 9

What is the AUC a measure of?
(in oral Cp vs. t curve)

Back 9

The extent of absorption.

Front 10

If absorption is greater for one drug product that another, then more of the ? product should appear in the urine.

Back 10

More of the first product.

Front 11

For most drugs elimination is what?

Back 11

First-order

Front 12

How much time should be allowed for the collection of the amount of absorbed drug in the urine?

Back 12

About 5 half-lives.

Front 13

Au towards infinity is the total amount of what? What is this a measure of?

Back 13

The absorbed drug that is ultimately excreted unchanged. It is a measure of the extent of drug absorption.

Front 14

What does the idea of relative bioavailability compare?

Back 14

This compares the extent of absorption of a test product (generic drug) with a standard reference product. It is the systemic availability of a drug in a given drug product relative to its availability in a standard formulation (such as the Reference Listed Drug).

Front 15

If two products are given at the same dose how do you determine relative bioavailability?

Back 15

Rel. Bioavail. = [AUC]test/[AUC]reference

OR

Rel. Bioavail. = (Du towards infinity)test/(Du towards infinity) reference

Front 16

For two products, if the doses are not the same how do you determine relative bioavailability?

Back 16

Rel. Bioavail. = ([AUC]test/test dose)/([AUC]reference/reference dose)

OR

Rel. Bioavail. = ([AUC]test/AUC reference)(reference dose/ test dose)

Front 17

A high rel. bioavailability means what about two products?

Back 17

They may be considered bioequivalent.

Front 18

Bioavailability does not necessarily mean what?

Back 18

It does not necessarily mean that either product is well absorbed.

Front 19

What is absolute bioavailability a reference to?

Back 19

It is a reference to the fraction of the oral dose (of an individual product) that is absorbed.

Front 20

How do you figure out the absolute bioavailability for the same drug dose given po verses IV?

Back 20

Absolute bioavailability = [AUC]oral/[AUC]iv

Front 21

How do you figure out the absolute bioavailability for the same drug given at different doses po verses IV?

Back 21

Absolute bioavailability = ([AUC]oral/AUCiv)(iv dose/ oral dose)

Front 22

Bioavailability studies try to assure what?

Back 22

That standards of effectiveness of a drug are met (such as identity, strength, and purity).

Front 23

What does the FDA require for new generic products?

Back 23

FDA requires in vitro and/or in vivo studies of bioavailability along with essential pharmacokinetic parameters are met. These are also reqd for new formulations of old drugs. These tests test for things such as half-life, rates of absorption, excretion and metabolism.

Front 24

Data from bioavailability studies help determine appropriate what?

Back 24

Dose regimens.

Front 25

Bioequivalent drug products show what?

Back 25

Similar bioavailability when studied under similar conditions.

Front 26

How is bioequivalence demonstrated?

Back 26

Bioequivalence is demonstrated by establishing that no 'statistical difference' exists among Cmax, tmax, and AUC for the test and reference products.

Front 27

What is ANOVA aka?

Back 27

Analysis of Variance

Front 28

What is ANOVA used for?

Back 28

ANOVA is a commonly used test (level of probability of > 0.05 and a power of 80% certainty). The avg parameter of the test product should be within 20% of that of the reference product.

Front 29

How does the FDA define bioequivalence?

Back 29

The RATE and EXTENT of absorption of the test drug DO NOT SHOW A SIG DIFFERENCE from the rate and extent of absorption of the reference drug when administered at the same molar dose of therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses.

OR

Where there is NO DIFFERENCE IN THE EXTENT of absorption, but a SIG DIFFERENCE IN THE RATE of absorption that is intentional, reflected in the label and is medically significant.

Front 30

What does the typical bioequivalency study consist of?

Back 30

Typically single-dose (usually following an overnight fast), two treatment, randomized cross over design. A plasma sample is take just before the dose and at regular intervals thereafter. Food intervention studies and multiple-dose studies are sometimes performed.

Front 31

What is the Latin square in a bioequivalent study?

Back 31

Each subject receives each drug product only once, with sufficient time between product administrations to allow for:

1. Full description of Cmax, tmax, and AUC

2. Elimination of product from the body

Front 32

What is a replicated crossover design in a bioequivalent study?

Back 32

Estimates within-subject variance for both products. FDA recommends a four-period, two-sequence, two-formulation design.

Front 33

What is a generic substitution?

Back 33

Dispensing an unbranded product or a different brand in place of a prescribed product.

Front 34

Generic substitutions have the ? dosage form, ? active ingredient, and ? manufacturers.

Back 34

Generic substitutions have the same dosage form, same active ingredient, and different manufacturers.

Front 35

Generic substitution has to be permitted by whom?

Back 35

The prescriber.

Front 36

What is the FDA published list of drug products?

Back 36

The Orange Book ('Approved Drug Products with Therapeutic Equivalence Evaluations)

Front 37

What does the letter A represent in the orange book?

Back 37

Deemed therapeutically equivalent.

Front 38

What does the letter B represent in the orange book?

Back 38

Inadequate evidence of bioequivalence.

Front 39

?-letter codes are used in the orange book.

Back 39

Two-letter codes are used.

Front 40

Define the term 'pharmaceutical alternatives'?

Back 40

The same therapeutic entity but presented as different salts, complexes or esters. Also different dosage forms (eg. elixirs, caps, and tablets) and strengths by a single manufacturer.

Front 41

Define the term 'pharmaceutical equivalents'?

Back 41

Same active ingredient, same amount of it, same dosage form for the same route of administration. Must meet same uniformity, disintegration and dissolution rates where applicable. May differ in features such as packaging, shape, color, release mechanism, excipients and some labeling details.

Front 42

The process of dispensing a pharmaceutical alternative in place of a prescribed product needs what?

Back 42

Prescribe approval.

Front 43

Define the term therapeutic alternatives.

Back 43

Different active ingredients share same indications and used for same therapeutic objectives (ex. ibuprofen verses ASA)

Front 44

Define the term 'therapeutic equivalents'?

Back 44

Expected to have the same clinical effect and safety profile.

Front 45

Therapeutic substitution involves the use of a what?

Back 45

Therapeutic alternative.

Front 46

The drug review process contrast what?

Back 46

NDAs and ANDAs

Front 47

What must NDAs have? What must ANDAs have?

Back 47

NDAs must have animal and clinical data along with bioavailability data. ANDAs do not need these but must have bioequivalence data.

Front 48

The biopharmaceutics classification system is used to predict what?

Back 48

It is used to predict in vivo absorption based on solubility and permeability characteristics.

Front 49

What is Jw?

Back 49

Drug flux (mass/area/time)

Front 50

What is Pw?

Back 50

Permeability of membrane.

Front 51

What is Cw?

Back 51

Drug concentration at intestinal membrane surface.

Front 52

What is the eqn to find Jw?

Back 52

Jw = (Pw)(Cw)

Front 53

Biopharmaceutics is the study of what relationship?

Back 53

The study of the rel. between the nature and intensity of the biological effects produced in humans (or animals) AND the physicochemical properties of the drug formulation administered. Some authorities include pharmacokinetics as a branch or biopharmaceutics.

Front 54

List 4 biopharmaceutic considerations?

Back 54

1. The stability of the drug.

2. The release of the drug from the product.

3. The rate of dissolution or release at the site of absorption.

4. The systemic absorption of the drug.

Front 55

List 5 formulation properties.

Back 55

1. The type of dosage form.

2. The pharmaceutical process used in preparing dosage form.

3. The presence (or absence) of adjuncts with the drug.

4. The physical state, particle size and surface area of drug.

5. The chemical nature of the drug (salt, complex, ester, etc.)

Front 56

A solid oral dosage form needs to ? to release the drug.

Back 56

A solid oral dosage form needs to disintegrate to release the drug.

Front 57

The USP has a standard ? test. This is a component of what?

Back 57

The USP has a standard disintegration test. This is a component of the quality control process during tablet manufacture.

Front 58

What does not have to satisfy USP disintegration criteria?

Back 58

Chewable tablets, modified-release tablets and troches.

Front 59

Describe the process of dissolution from the drug particle to the bulk solvent?

Back 59

1. Dissolution at the particle surface.

2. Formation of saturated solution (stagnant layer) around particle.

3. Dissolved drug diffuses from stagnant layer to the bulk of the solvent (from region of high concentration to a region of low concentration).

Front 60

The rate of dissolution (following ?) can control what?

Back 60

The rate of dissolution (following disintegration) can control the rate of absorption.

Front 61

In the GI tract, a drug would be considered to be dissolving in an ? medium.

Back 61

Dissolving in an aqueous medium.

Front 62

FDA dissolution tests may be used to to predict what?

Back 62

Bioavailability.

Front 63

The FDA uses dissolution tests to predict bioavailability. What does the USP do?

Back 63

The USP also sets testing standards (a certain percentage of the labeled drug amount must dissolve in a specified period at the specified temperature) for the dissolution and release of many drugs.

Front 64

What do dissolution tests help discover?

Back 64

Possible problems with the product formulation, batch-to-batch variations. They can help predict in vivo performance.

Front 65

What affects drug dissolution?

Back 65

The physicochemical nature of a drug and the excipients used, as well as the manufacturing method.

Front 66

What equation governs the rate of dissolution?

Back 66

The Noyes-Whitney equation.

dC/dt = (DA/h)(Cs - C)

D = diffusion rate constant

A = surface area of the particle

Cs = concentration of drug in stagnant area

h = thickness of stagnant layer

Front 67

What is the temperature in vivo? What does an increase in temperature result in?

Back 67

37C. An increase results in a higher D (diffusion rate constant).

Front 68

What kind of agitation occurs in vivo? What does an increase in agitation result in?

Back 68

Mainly peristalsis. An increase in agitation results in a smaller h (thickness of stagnant layer).

Front 69

What might excipients do?

Back 69

Excipients may alter the medium in which the drug dissolves.

Front 70

Give 4 examples of excipients that may alter the medium in which a drug dissolves?

Back 70

1. Suspending agents make the medium more viscous and so decrease the dissolution rate.

2. Certain coating material form cross-links when they age and so decrease dissolution.

3. Lubricants repel water and so can reduce dissolution if present in large amounts.

4. Sodium Bicarb. (and some others) change the medium pH. For example, ASA will dissolve rapidly in such a reactive medium.

Front 71

Excipients may be added to do what to the rate and extent of absorption?

Back 71

They may be added to either retard or increase the rate and extent of absorption.

Front 72

List 4 drug physciochemical properties.

Back 72

1. pH and solubility.

2. pH and stability.

3. Particle size

4. Polymorphs

Front 73

Describe the physicochemical property of 'pH and solubility'?

Back 73

A basic drug is more soluble in the acidic medium of the stomach; an acidic drug is more soluble in the intestines. Excipients may be added to make modifications; buffering agents may be added to modify the release rate of a fast dissolving drug.

Front 74

Describe the physicochemical property of 'pH and stability'?

Back 74

pH may impact stability if a drug is decomposed via acid or base catalysis.

Front 75

Describe the physicochemical property of particle size?

Back 75

For poorly soluble drugs this is very important because dissolution occurs at the particle surface. Thus particle size and particle size distribution impact absorption.

Front 76

Describe the physicochemical property of polymorphs?

Back 76

Polymorphs have the same chemical structure but different physical properties. Some polymorphic forms may be more aqueous soluble than others.

Front 77

List 6 drug product considerations?

Back 77

1. Safety and efficacy

2. Desired Cp

3. Bioavailability

4. Dose

5. Route of administration

6. Compliance

Front 78

Concerning the safety and efficacy of drugs what must excipients not add?

Back 78

toxicity

Front 79

How do you achieve the desired Cp for a drug product?

Back 79

The formulation should be such that the release rate and the dose should help achieve the Cp (for acute illness drugs, the release rate should be high; for prophylactic drugs, ER forms could be appropriate).

Front 80

How is bioavailability taken into consideration for a drug product?

Back 80

Steps should be taken to preserve the stability of the drug (eg. use of enteric coating or buffers); for drugs subject to first pass effects, alternative routes of administration could be used of the dosage adjusted.

Front 81

How is dose taken into consideration for a drug product?

Back 81

This depends on the drug's potency and the Vd. Because of individual variations in pharmacokinetic parameters, different dose strengths of the product could be helpful. Additionally, tablets scored to facilitate breaking could be helpful.

Front 82

What can result from different routes of administration?

Back 82

A significant difference in responses.

Front 83

What three things might be considered when dealing the compliance for a drug product?

Back 83

1. Product size: Oddly shaped or large oral products could present swallowing difficulties with some patients.

2. Product Taste and Odor: should be agreeable to facilitate compliance

3. Extended-release products could aid compliance.