Bioequivalence 3

Question 1

What should the dose of the drug be for SOD?

Answer 1

highest dose approved for innovator (R)

Question 2

What are the advantages of PK-BE studies?

Answer 2

no disease problems
control of potential confounding factors
no polypharmacy

Question 3

What is the most common study design for PK-BE?

Answer 3

SOD

Question 4

What are the disadvantages of PK-BE studies?

Answer 4

cannot do PD study (since healthy)

Question 5

Which PK parameters should be tabulated for each subject-formulation combination in PK-BE?

Answer 5

AUCt
AUCi
AUCt/AUCi
Cmax
Tmax
terminal disposition rate constant
t1/2
where time to onset is important, the following should be reported:
-AUC to Tmax of the reference product, calculated for each study subject

Question 6

The analysis of any comparative bioavailability study should have what included?

Answer 6

randomization scheme for the design
summary of drug concentrations at each sampling time for each subject for both T and R
summary of the estimates of the parameters for T and R
-including means, SDs, CVs
formal statistical analysis of the relevant parameters with comparisons of T to R

Question 7

What is compared when establishing BE?

Answer 7

compare T and R metrics
-Cmax and AUC

Question 8

Differentiate Cmax and AUC.

Answer 8

Cmax
-influenced by rate and extent of absorption
-measure of peak exposure
-metric recommended to evaluate rate of absorption
AUC
-influenced by extent of absorption
-measure of total exposure
-metric recommended to evaluate extent of absorption

Question 9

What is ANOVA?

Answer 9

analysis of variance
-can deal with several sources of variability
-between subject variability (BSW) and within subject variability (WSV)
BE studies concerned mostly with what happens when subject takes drug on more than one occasion, want info on WSV

Question 10

What is BSV?

Answer 10

variability associated with product, period, sequence, subject
-can be high due to biological variation but WSV also contributes to BSV

Question 10

What is residual variance?

Answer 10

residual or error mean square in ANOVA
estimates the WSV

Question 11

What are the several variance components of residual variance?

Answer 11

WSV in PK (day to day variation in ADME)
analytical variability
within product variability (tablet to tablet)
subject by formulation interaction
-occurs when a subject shows a markedly different response to two formulations in terms of Cmax and AUC
unexplained random variation

Question 12

What is used to test null hypothesis in ANOVA?

Answer 12

F test statistic

Question 13

What was realized about ANOVA test of the simple null hypothesis?

Answer 13

regulatory bodies realized it was inappropriate

Question 14

Describe the confidence interval approach to statistical analysis for BE.

Answer 14

CI used as BE test to evaluate whether the mean amount of drug absorbed using test is close to that of reference
CI calculated from WSV
-smaller the variability the narrower the CI
HC requires 90% CI to be calculated for natural log of the difference-in-mean of the AUC

Question 15

What is the bioequivalence range?

Answer 15

the standard equivalence criterion is 80-125% for the 90% CI of the ratio of the geometric means
the 90% CI must fall entirely within the BE limits of 80-125%

Question 16

What difference in Cmax or AUC between two formulations is suggested by physicians to have no clinical significance?

Answer 16

20%

Question 17

What are the basic steps involved in statistical analysis for BE determination?

Answer 17

BE metrics are naturally logarithmically transformed and subjected to ANOVA analysis
the mean difference between the transformed data for each metric are then calculated
standard error of the difference in the means is calculated
high and low bounds of the CI about the mean difference of the transformed data is calculated

Question 18

What should be included in the reported results for statistical analysis of BE?

Answer 18

arithmetic means and CVs for each product
testing and estimates for fixed and random effects
AUCt and Cmax ratios of geometric means for test vs reference products
the appropriate CI about the parameter being analysed

Question 19

What data is required for the two products for uncomplicated drugs?

Answer 19

AUCt, AUCi
Cmax, Tmax
k, t1/2