Bioequivalence 4

Question 1

True or false: oral MR products require different guidelines

Answer 1

true

Question 2

Why do MR products require different regulations?

Answer 2

increased likelihood that increased between-subject variability in BA will occur, including dose-dumping
increased risk of AE depending upon site of release, absorption, or both

Question 3

How should BE be demonstrated for MR products if its SOD?

Answer 3

under both fasted and fed conditions

Question 4

What kind of volunteers should be used for MR studies if its SOD?

Answer 4

healthy volunteers
-disease populations causes increased differences in absorption and disposition

Question 5

What kind of design is used for MR products if its SOD?

Answer 5

four-period crossover trial (replicate design)
-each subject takes T and R twice

Question 6

What are the BE standards for MR products if its SOD?

Answer 6

90% CI around the GMR for AUC of T and R should be within the BE limits of 80-125% in fasting and fed states
-AUClast may be evaluated provided it is ~80% of the extrapolated area
GMR of Cmax for T and R should be within 80-125% in fed and fasted states
-no 90% CI required

Question 7

True or false: steady states are required for multiple oral dose MR study

Answer 7

false

Question 8

What kind of conditions are multiple oral dose MR studies conducted under?

Answer 8

fasting conditions
-unless safety of subjects requires that drug product be administered with a meal

Question 9

What are the BE requirements for multiple oral dose MR study?

Answer 9

90% CI around the GMR for AUC of T and R should be within be within BE limits of 80-125%
GMR of Cmax at SS for T and R should be within 80-125%
-no 90% required
GMR of Cmin at SS for T and R should not be less than 80%

Question 10

When is food-effect BA and fed BE conducted?

Answer 10

new drugs/drug products during the IND
-type and magnitude of food effects largely unpredictable due to number of complex factors
fed BE studies conducted for ANDA to demonstrate BE to R under fed conditions
use high calorie and high fat meals, has greatest effect on GIT physiology

Question 11

What strength of drug should be used for food-effect BA and fed BE studies?

Answer 11

highest strength of drug product

Question 12

How should food-effect and fed BE studies be conducted?

Answer 12

following 10h fast administer drug 30 min after start of meal with 240ml water
no food allowed for 4h post dose

Question 13

What was the effect of food on BE of OROS methylphenidate?

Answer 13

no effect

Question 14

How should bioavailability be studied in drugs with serious toxicity within the normal dosage range?

Answer 14

at steady-state

Question 15

What kind of study design is used for drugs with serious toxicity within the normal dosage range?

Answer 15

parallel

Question 16

How should the comparative bioavailability study be conducted for drugs with greater than proportional increases in AUC with increasing dose?

Answer 16

comparative bioavailability study should be conducted on at least the highest strength

Question 17

How should the comparative bioavailability study be conducted for drugs with saturable absorption and resulting in less than proportional increases in AUC with increasing dose?

Answer 17

comparative bioavailability study should be conducted on at least the lowest strength

Question 18

How should the comparative bioavailability study be conducted for drugs with limited solubility of the API and resulting in less than proportional increases in AUC with increasing dose?

Answer 18

comparative bioavailability study should be conducted at least the lowest strength in the fasted state and in the highest strength in both the fasted and fed states

Question 19

Drugs with how long of a t1/2 require BE guideline modification?

Answer 19

> 24h

Question 20

What is the BE criteria for drugs with a long t1/2?

Answer 20

same BE criteria except for the following:
-AUC 0-72 will be used as comparison parameter
-require very long washout periods so crossover may be replaced with parallel design, SS studies, or use of stable isotopes

Question 21

What are additional BE requirements in addition to standard requirements for drugs with an important time of onset of effect or rate of absorption?

Answer 21

AUCtmax of R to T should be within 80-125%

Question 22

What are examples of critical dose drugs?

Answer 22

cyclosporine
digoxin
flecainide
lithium
phenytoin
sirolimus
tacrolimus
theophylline
warfarin

Question 23

How does Health Canada define a critical dose drug?

Answer 23

drugs where comparatively small differences in dose or concentration lead to dose and concentration dependent serious therapeutic failures and/or serious AE which may be persistent, irreversible, slowly reversible, or life threatening, which could result in inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability, incapacity or death. AE that require significant medical intervention to prevent one of these outcomes are also considered to be serious

Question 24

What are the BE requirements for critical dose drugs?

Answer 24

90% CI around the GMR for AUC of T and R should be within BE limits of 90-112%
90% CI around the GMR for Cmax of T and R should be within the BE limits of 80-125%

Question 25

In what state should BE studies be conducted for critical dose drugs?

Answer 25

fasted and fed states

Question 26

True or false: steady state studies are required for critical dose drugs

Answer 26

false

Question 27

Which patients might we conduct studies for critical dose drugs in if steady state is required?

Answer 27

patients who are already receiving the drug as part of their treatment, rather than in healthy subjects

Question 28

How should bioavailability be studied for critical dose drugs if steady state is required?

Answer 28

during a dosing interval at steady state

Question 29

Which study design is preferred for critical dose drugs?

Answer 29

parallel

Question 30

What should the 90% CI of the relative mean Cmin be if required for a critical dose drug?

Answer 30

80-125%

Question 31

What are the PK parameters that need to be reported and assessed for a combination product?

Answer 31

those normally required of each drug if it were in the formulation as a single entity

Question 32

What causes the variability in highly variable drug products?

Answer 32

inherent variability may be due to drug (HVD) or to the formulation factors of the product (HVDP)
-HVD when within-subject coefficient of variation (CV) of the applicable AUC for the reference product is greater than 30%

Question 33

What are the BE requirements for highly variable products?

Answer 33

the 90% CI of the relative mean AUC of the test to reference product should be within the following limits:
-80-125%, if CV < 30%
-66.7-150%, if CV > 57.4%
relative mean AUC of the T to R product should be within 80-125%
relative Cmax of T to R product should be within 80-125%

Question 34

What dose should be used for drugs with measurable endogenous levels?

Answer 34

drug doses should be high enough to differentiate exogenous levels from endogenous levels

Question 35

How should T and R be administered for drugs with measurable endogenous levels?

Answer 35

at the same time of day to reduce the potential contribution of diurnal variation

Question 36

What should be used in the statistical analysis of drugs with measurable endogenous levels?

Answer 36

baseline-corrected plasma concentrations
-subtract the estimated endogenous baseline concentration from each post-dose concentration
-individual baseline levels be calculated in each period prior to dosing-fluctuations in endogenous concentrations