Bioequivalence (3) [Complicated Drugs]

Question 1

T or F: We can use average BE studies for complicated drugs.

Answer 1

F

Average BE studies are used only for uncomplicated drugs.

Question 2

What kinds of drugs require modifications in BE study design? (9)

Answer 2

1. Oral modified release (MR) products
2. When drug is affected by fed state
3. Drugs w/ narrow therapeutic windows (critical dose drugs)
4. Highly variable drugs (HVD)
5. Drugs that have non-linear pharmacokinetics
6. Drugs w/ long t1/2’s
7. Drugs w/ important time of onset of effect OR rate of absorption
8. Drugs for which urine conc data is used
9. When drug’s metabolites affect BE

Question 3

What’s a major concern of modified release dosage forms?

Answer 3

Dose dumping

Question 4

What is being compared in a Single Oral Dose MR study?

Answer 4

Single dose of generic MR and innovator’s conventional formulation that the generic aims to replace

Question 5

T or F: 90% confidence interval is required for AUC in a Single Oral Dose MR study.

Answer 5

T

Question 6

What are the BE limits for the 90% confidence interval in Single Oral Dose MR studies?

Answer 6

80-125% (log transformed geometric mean ratios of AUC)

Question 7

T or F: 90% confidence interval is required for Cmax in a Single Oral Dose MR study.

Answer 7

F

MR oral drugs vary greatly wrt Cmax

Question 8

T or F: Multiple Oral Dose MR studies are not req’d for fmlations used at a dosing interval likely to lead to accumulation.

Answer 8

F

They ARE req’d since they might cause accumulation.

Question 9

T or F: Multiple Oral Dose MR studies are req’d for fmlations used at a dosing interval likely to lead to accumulation.

Answer 9

T

Question 10

For Multiple Oral Dose MR studies, 1. what % CI is used for the GMR of the AUC of T and R drugs, and 2. what are the BE limits within which the CI should be?

Answer 10

1. 90% CI2. 80-125%

Question 11

For Multiple Oral Dose MR studies, GMR of Cmax at steady state for T and R should be within…

Answer 11

80-125%

Question 12

For Multiple Oral Dose MR studies, GMR of Cmin at steady state for T and R should not be less than…

Answer 12

80%

Question 13

T or F: Geometric mean ratio (GMR) is more stringent than 90% CI’s

Answer 13

F

Question 14

T or F: 90% CI’s are more stringent than geometric mean ratios (GMR).

Answer 14

T

Question 15

When can we conclude BE under fed conditions for drugs affected by fed state?

Answer 15

When the 90% CI for the GMR b/w T and R drugs is between 80-125% for AUC and Cmax (i.e. same req as uncomplicated drugs)

Question 16

Small diffs in dose or conc lead to dose- and conc-dependent, serious therapeutic failures and/or serious adverse drug rxns. What category of drugs are being described here?

Answer 16

Critical Dose Drugs

Question 17

For Critical Dose Drugs, the 90% CI around the GMR for AUC of the T and R formulations should be within the BE limits of ______

Answer 17

90-112%

Question 18

For Critical Dose Drugs, the 90% CI around the GMR for Cmax of the T and R formulations should be within the BE limits of ______

Answer 18

80-125% (just like uncomplicated drugs)

Question 19

Why is it unethical to use healthy subjects in Critical Dose Drug studies?

Answer 19

There are likely to be side effects given the narrow therapeutic windows.

Question 20

A drug is considered to be “highly variable” when the ANOVA-CV is greater than ___%

Answer 20

30%

Question 21

What does ANOVA-CV describe in Highly Variable Drug studies?

Answer 21

Within-subject variability

Question 22

Linear or Non-Linear pharmacokinetics?When you can’t predict the AUC or Cp based on dose.

Answer 22

Non-linear PK

Question 23

Linear or Non-Linear pharmacokinetics?When you can predict the AUC or Cp based on dose.

Answer 23

Linear PK

Question 24

Drugs of what category will utilize AUC (0-72h) as a comparison parameter?

Answer 24

Drugs w/ long half lives

Question 25

Would crossover or parallel study designs be more appropriate for drugs w/ long half lives?

Answer 25

Parallel (due to long washout period)

Question 26

T or F: 90% CI for drugs w/ long half lives needs to be between 80-125%

Answer 26

T

Question 27

BE is commonly determined based on drug concs in the urine

Answer 27

F

V. rare, actually

Question 28

T or F: Critical dose drugs can be replaced by generics.

Answer 28

F

Due to v. narrow therapeutic window

Question 29

What is the role of metabolites in BE?

Answer 29

Not known (no consensus)

Question 30

T or F: Pharmaceutical equivalents can be equivalent in terms of the extent of absorption but not their rates of absorption.

Answer 30

T

Question 31

T or F: BE studies can be done with two test products (i.e. no reference/inventor product)

Answer 31

F

We must use the inventor’s product in BE studies