13 Bioequivalence

Discuss the statistical evaluation of bioequivalence

- 90% CI for both Cmax and AUC for the test product must be within 80-125% of the reference product - 80-125% does not mean drug levels can vary up to 45% - Levels must be consistent - Bioavailability of most generic drug differs from brand name by <4% - Variability between brand and generic is the same as variability between batches of the same brand-name drug

What is a first letter code and what does it mean?

- A: therapeutically equivalent to another pharmaceutically equivalent drug - B: no TE

Absolute bioavailability

- Compares oral dose vs. IV - Comparison of AUC of other routes with AUC by IV administration reveals whether any drug is lost during absorption

Pharmaceutical alternatives

Drug products contain the same active drug but have - Different salt forms - Different dosage strength (10mg vs 20mg) - Different type of dosage form (IR vs ER)

Identify what a BP code means?

active ingredients with potential BE concerns

Identify what a BD code means?

documented BE problems

Authorized generics

generics that are identical to the brand, made by brand company or subsidiary but repackaged for sale under the generic name

Identify what a BX code means?

insufficient date to determine BE

Bioavailability

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

What is a reference formulation?

- Every generic product is compared to a reference formulation - RLD: brand name product that was approved for particular drug/dosage form - Sometimes the RLD is no longer on the market - In these cases FDA assigns a reference standard (RS) to which all generics are compared

What is a second letter code?

- Provides additional information about the dosage form or actual/potential BE problem

Pharmaceutical equivalents

- Same active ingredients - Same strength or concentration - Same dosage form and route of administration May differ in characteristics such as - Shape - Release mechanism - Scoring - Excipients - Packaging - Expiration time - Labeling

Steps in determining therapeutic equivalency

1. Determine if you have pharmaceutical equivalents (same active ingredient, strength or concentration, dosage form, and route) 2. If products are pharmaceutically equivalent, look at the TE code provided in the Orange Book to determine if the products are BE 3. If the products are pharmaceutical equivalents and have the same TE code, they are TE

Identify when bioequivalence testing can be waived based on Biopharmaceutics Classification System (BCS) class

1. Manufacturers can submit for a waiver of in vivo testing of an IR product by use of the BSC - BSC Class I drugs are eligible for a waiver of in vivo BE testing 2. BE testing can be waived and in vitro dissolution testing substituted for drugs contained in dosage forms with the following properties - High solubility - High permeability - Rapid dissolution - Similar dissolution profile to brand product - Wide therapeutic window - Excipients used in dosage form used previously in FDA approved IR solid dosage forms 3. Large amount of evidence suggests a correlation between in vitro data and in vitro exposure

List the factors that can influence the bioavailability of a drug

1. Physiochemical properties of the drug substance - Salt form - Crystalline or amorphous form - Particle size 2. Pharmaceutical excipients 3. Dosage form characteristics - Disintegration rate - Dissolution time 4. Physiologic factors and patient characteristics - Gastric emptying time - Intestinal transit time - Gastric contents (foods, liquids, other drugs) - GI pH - Drug metabolism and transport

Two products are considered Bioequivalent if the 90% CI for both Cmax and AUCs fall within?

80-125%

An Rx is for Protonix. Based on the formulary, you dispense lansoprazole to the patient. This is an example of? A. Therapeutic substitution B. Generic substitution

A. Therapeutic substitution

Bioavailability of a drug can be influenced by? A. dissolution rate B. excipients in the dosage forms C. salt form of the drug D. shape of the dosage form

A. dissolution rate B. excipients in the dosage forms C. salt form of the drug

Differentiate between AUC, Cmax, and Tmax and understand how they are used to evaluate the rate and extent of drug absorption

AUC - Extent of absorption Cmax - Rate and extent of absorption Tmax - Rate of absorption

To be therapeutically equivalent drugs products must be? A. bioavailable B. both pharmaceutically equivalent and bioequivalent C. pharmaceutical equivalent D. bioequivalent

B. both pharmaceutically equivalent and bioequivalent

IF the first letter in a TE code is B, this means? A. formulation is bioavailable B. formulation is not therapeutically equivalent C. formulation is therapeutically equivalent

B. formulation is not therapeutically equivalent

Omeprazole 20 mg DR caps & Omeprazole 20 mg DR tabs are considered? A. therapeutic equivalents B. pharmaceutical alternatives C. bioequivalent D. pharmaceutical equivalent

B. pharmaceutical alternatives

Describe the methods that go into determining if a drug product is bioequivalent to another product

Bioequivalence (BE): two drug products do not differ significantly in their rate and extent of absorption - In vivo PK studies most used to determine BE - Assesses relative bioavailability of the test formulation to the reference formulation - Conducted in randomized crossover design in healthy volunteers - Plasma levels of drug are measured over time - Healthy volunteers are randomized to take one dose of a reference formulation and then one dose of test formulation without washout periods in between - Plasma samples analyzed for drug concentrations - Calculation of AUC, Cmax - Data is log transformed - 90% confidence intervals calculated

Therapeutic equivalence

Both pharmaceutically equivalent and bioequivalent - Pharmaceutical equivalent: same active ingredients, strength/concentration, dosage form, and route - Bioequivalent products have comparable bioavailability - Can be substituted or interchanged - Denoted by the FDA by TE codes - TE codes published in orange book

Which describes the formulation of the drug that all other formulations are compared to? A. test formulation B. pharmaceutically equivalent C. reference listed drug D. therapeutically equivalent

C. reference listed drug

Which of the following is NOT a criteria to determine pharmaceutical equivalence? A. same dosage form and route B. same active ingredient C. same release mechanism D. same strength/concentration

C. same release mechanism

Which BCS class of drugs are eligible for a biowaiver of in vivo BE studies?

Class 1

Identify what an AA code means?

No BE problems in conventional dosage forms

Describe when it is not appropriate to complete generic substitution for a drug product

Pharmaceutically equivalent drug products may differ in characteristics such as - Shape - Release mechanism - Labeling - Scoring - Excipients Generic substitution is not appropriate if one of the above is an important consideration

Given Orange Book data, determine whether two products are therapeutically equivalent and if generic substitution can be made. 3. Look at the example and determine if they are TE

Pharmaceutically equivalent: No BE (same TE code): No Therapeutically equivalent: No

Given Orange Book data, determine whether two products are therapeutically equivalent and if generic substitution can be made. 2. Look at the example and determine if they are TE

Pharmaceutically equivalent: Yes BE (same TE code): No Therapeutically equivalent: No

Given Orange Book data, determine whether two products are therapeutically equivalent and if generic substitution can be made. 1. Look at the example and determine if they are TE

Pharmaceutically equivalent: Yes BE (same TE code): Yes Therapeutically equivalent: Yes

Authorized generics are identical to the brand name product. True or False

True

Drug products that are therapeutically equivalent can be substituted for each other. True or False

True

Is this product bioequivalent to the reference? Bioequivalence Comparison of Generic (Test) and Brand (Reference) Drug Products (Log Transformed Data)

Yes, BE, Cmax, and AUC are within 80-125% - tmax does not matter to determine product BE

Relative bioavailability

compares two oral doses with each other

Identify what an AB code means?

meets necessary BE requirements, shown to have no BE problems through in vivo or in vitro evidence

Identify what an AB1/AB2/AB3 code means?

multiple sources of drug are available, but these sources are not considered TE to each other - two or more RLDs that are not BE to each other

A TE code BP mean?

product has potential bioequivalence problems

Reference listed drug

the brand name product that was first approved for that particular drug/dosage form

Bioequivalence:

two drug products (test vs. reference) do not differ significantly in their rate and extent of absorption