T2 - Bioavailability / Bioequivalence

Question 1

What is pharmaceutical equivalents?

Answer 1

Drug products that contain identical amounts (dose) of an identical API (including the same salt or ester form) in identical dosage form, but not necessarily containing the same inactive ingredients.

Question 2

What is pharmaceutical alternatives?

Answer 2

Drug products that contain the identical therapeutic API, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester.

Question 3

What is therapeutic equivalents?

Answer 3

Drug products are considered to be therapeutic equivalents only if they are pharmaceutical equivalents with the same clinical effect and safety profile for which bioequivalence has been demonstrated.

Question 4

What is the requirement of having multi source drug products?

Answer 4

To facilitate the decision of therapeutic equivalency between pharmaceutically equivalent drug products, FDA requires bioequivalence testing

Question 5

What is the Orange book?

Answer 5

1. Identifies approved drug products by the FDA under the Federal Food, Drug, and Cosmetic Act
2. Contains therapeutic equivalence evaluations for approved multi source drug products

Question 6

What is the purpose of the therapeutic equivalence code?

Answer 6

Allows users to determine quickly whether the FDA has evaluated a particular approved product as therapeutically equivalent to other pharmaceutically equivalent products and to provide additional information on the basis of FDA’s evaluations.

Question 7

What are the Biopharmaceutics Classification System of FDA?

Answer 7

Class 1: High Solubility – High Permeability
Class 2: Low Solubility – High Permeability
Class 3: High Solubility – Low Permeability
Class 4: Low Solubility – Low Permeability

Question 8

How are drugs categorized according to the FDA?

Answer 8

Drug’s aqueous solubility and intestinal permeability parameters

Question 9

What BCS classes do not require BA/BE studies?

Answer 9

Classes 1 and 3 have a granted biowaver

Question 10

What BCS causes require BA/BE studies?

Answer 10

Class 2 and 4

Question 11

What is bioavailability?

Answer 11

The rate and extent to which the active ingredient is absorbed from the drug product and becomes available at the site of action

Question 12

What factors influence bioavailability?

Answer 12

1. The method of manufacture or compounding, particle size, crystal form (polymorph) of the drug substance,
2. The properties of the excipients used to formulate the dosage form, and physical changes as the drug product ages.

Question 13

What is the rationale for bioavailability studies?

Answer 13

1. An estimate of the fraction of administered dose (usually after oral administration but not limited to) that is absorbed into the systemic circulation.
2. Indirect information regarding the first-pass metabolism of the drug and the role of transporters such as p-glycoproteins on the drug.
3. Information on the effect of food and other nutrients on drug absorption.
4. Information on distribution and elimination characteristics of the drug.
5. Information regarding the performance of the formulation.

Question 14

What are bioavailability studies used for?

Answer 14

To compare different dosage forms of drugs administered at different routes to understand which has the most desirable absorption pattern

Question 15

How do we calculate absolute bioavailability?

Answer 15

Question 16

What is bioequivalence?

Answer 16

The absence of a significant difference in the rate and extent to which the active ingredient in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

Question 17

How is plasma concentration used to determine bioequivalence?

Answer 17

Considered a surrogate for the concentration at the site of action for a systemically acting drug

Question 18

What is the purpose of bioequivalence studies?

Answer 18

1. Compare the bioavailabilities of different formulations, drug products, or batches of the same drug
2. Determination of the therapeutic equivalence between pharmaceutically equivalent generic drug product and the corresponding reference drug.
3. Provide information on product quality and performance when there are changes in components, composition, and method of manufacture after approval of the drug product

Question 19

What are bioequivalent drug products?

Answer 19

Drugs whose bioavailabilities don’t show a significant difference when administered at the same dose and route of administration

Question 20

How do we calculate relative bioavailability?

Answer 20

Question 21

What is relative bioavailability?

Answer 21

Equivalent doses of a drug, when fully absorbed, produce comparable AUCS

Question 22

What are benefits of calculating absolute bioavailability?

Answer 22

Comparing the effectiveness of a drug’s oral and intravenous dosage forms

Question 23

How does relative bioavailability studies used for drug development?

Answer 23

1. Assess how the new formulation impact bioavailability
2. Assess how food effects bioavailability
3. Assess drug-drug interactions

Question 24

What is the reference product of testing bioavailability?

Answer 24

An oral solution when testing a new oral formulation product

Question 25

What is the most common experimental plan to compare bioavalibilities of 2 drug products?

Answer 25

Crossover design study

Question 26

What is crossover design study?

Answer 26

Wherein study patients take the test and reference drug products sequentially between a washout period of the drug out of their system

Question 27

What factors are assessed that demonstrate the rate and extent of drug absorption from bioequivalence drug products?

Answer 27

Cmax and AUC are assessed and compared for statistically significant difference on log-transformed data between the test and reference drug products. Also, Tmax is reported.

Question 28

What is the optimal ratio for bioequivalence?

Answer 28

80-125%

Question 29

What is Cmax?

Answer 29

The observed peak concentration of a drug in the plasma following the oral dose of the drug

Question 30

Why do we collect Cmax?

Answer 30

To compare peak exposure achieved by the dose

Question 31

What is the primary objective of dosing a drug to patient?

Answer 31

To achieve the minimum effective concentration (MEC) without crossing the minimum toxic concentration (MTC)

Question 32

What is Tmax?

Answer 32

Reflects the rate of drug absorption from the formulation (time of peak concentration of drug in plasma)

Question 33

Why do we collect Tmax?

Answer 33

1. To compare rate of absorption
2. Determines the time needed for the MEC to be reached
3. Affects the period over which the drug enters the blood stream

Question 34

What happens if the rate of drug absorption changes?

Answer 34

The values of both Cmax and Tmax change as well

Question 35

What does AUC represent?

Answer 35

The total amount of drug absorbed into the circulation (plasma)

Question 36

Why is the AUC measured?

Answer 36

To compare total exposure or extent of drug absorption

Question 37

What are the types of bioavailability data submissions required by the FDA?

Answer 37

1. New drug applications (NDAs)
2. Abbreviated new drug applications (ANDAs)
3. Supplemental applications

Question 38

What are supplemental applications used for?

Answer 38

1. Changes in manufacturing process, product formulation, or dosage strength.
2. Changes in labeling to provide for a new indication for use of the drug product.
3. Changes in labeling to provide for a new or additional dosage regimen for a special patient population.

Question 39

When is the linear-log trapezoidal method used?

Answer 39

1. When plasma concentrations increasing (absorption phase), linear is used
2. When plasma concentrations decreasing (elimination phase), log is used