Bioequivalence (3) [Complicated Drugs] Flashcards
T or F: We can use average BE studies for complicated drugs.
F
Average BE studies are used only for uncomplicated drugs.
What kinds of drugs require modifications in BE study design? (9)
- Oral modified release (MR) products
- When drug is affected by fed state
- Drugs w/ narrow therapeutic windows (critical dose drugs)
- Highly variable drugs (HVD)
- Drugs that have non-linear pharmacokinetics
- Drugs w/ long t1/2’s
- Drugs w/ important time of onset of effect OR rate of absorption
- Drugs for which urine conc data is used
- When drug’s metabolites affect BE
What’s a major concern of modified release dosage forms?
Dose dumping
What is being compared in a Single Oral Dose MR study?
Single dose of generic MR and innovator’s conventional formulation that the generic aims to replace
T or F: 90% confidence interval is required for AUC in a Single Oral Dose MR study.
T
What are the BE limits for the 90% confidence interval in Single Oral Dose MR studies?
80-125% (log transformed geometric mean ratios of AUC)
T or F: 90% confidence interval is required for Cmax in a Single Oral Dose MR study.
F
MR oral drugs vary greatly wrt Cmax
T or F: Multiple Oral Dose MR studies are not req’d for fmlations used at a dosing interval likely to lead to accumulation.
F
They ARE req’d since they might cause accumulation.
T or F: Multiple Oral Dose MR studies are req’d for fmlations used at a dosing interval likely to lead to accumulation.
T
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?
- 90% CI2. 80-125%
For Multiple Oral Dose MR studies, GMR of Cmax at steady state for T and R should be within…
80-125%
For Multiple Oral Dose MR studies, GMR of Cmin at steady state for T and R should not be less than…
80%
T or F: Geometric mean ratio (GMR) is more stringent than 90% CI’s
F
T or F: 90% CI’s are more stringent than geometric mean ratios (GMR).
T
When can we conclude BE under fed conditions for drugs affected by fed state?
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)
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?
Critical Dose Drugs
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 ______
90-112%
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 ______
80-125% (just like uncomplicated drugs)
Why is it unethical to use healthy subjects in Critical Dose Drug studies?
There are likely to be side effects given the narrow therapeutic windows.
A drug is considered to be “highly variable” when the ANOVA-CV is greater than ___%
30%
What does ANOVA-CV describe in Highly Variable Drug studies?
Within-subject variability
Linear or Non-Linear pharmacokinetics?When you can’t predict the AUC or Cp based on dose.
Non-linear PK
Linear or Non-Linear pharmacokinetics?When you can predict the AUC or Cp based on dose.
Linear PK
Drugs of what category will utilize AUC (0-72h) as a comparison parameter?
Drugs w/ long half lives
Would crossover or parallel study designs be more appropriate for drugs w/ long half lives?
Parallel (due to long washout period)
T or F: 90% CI for drugs w/ long half lives needs to be between 80-125%
T
BE is commonly determined based on drug concs in the urine
F
V. rare, actually
T or F: Critical dose drugs can be replaced by generics.
F
Due to v. narrow therapeutic window
What is the role of metabolites in BE?
Not known (no consensus)
T or F: Pharmaceutical equivalents can be equivalent in terms of the extent of absorption but not their rates of absorption.
T
T or F: BE studies can be done with two test products (i.e. no reference/inventor product)
F
We must use the inventor’s product in BE studies
