Lecture 5: Bioequivalence testing of oral medicines II

Question 1

What are the data requirements for a bioequivalence report?

Answer 1

• name & signature of responsible investigators
• name & B/N of the products compared
• period of dates
• site of study
• details & results of assays & other tests
• deatails of how PK parameters were determined
• full protocol for the study (incl. written consent form)
• evidence that study protocol was approved by an appropriate ethics committee etc.

Question 2

What sort of data is required for evidence of a BE study?

Answer 2

comparative bioavailability data. The blood plasam or serum concentration-time curve provides the best measure of bioavailability for medicines with a systemic effect

Question 3

What is the bioavailability factor?

Answer 3

the ratio between total AUC of the test product and total AUC of the reference product.

Question 4

What is F?

Answer 4

the fraction of an administered dose that actually reaches systemic circulation

Question 5

What does an F value of 0 mean?

Answer 5

no drug absorption

Question 6

What does an F value of 1 mean?

Answer 6

complete drug absorption

Question 7

What is absolute bioavailability?

Answer 7

when an IV bolus injection is used as a reference.

This is because the entire administered dose is introduced directly to the systemic circulation. There are no absorption barriers to cross and is therefore considered totally bioavailable

Question 8

What is relative bioavailability?

Answer 8

the availability of a drug product as compared to similar dosage form of the SAME drug given in the SAME dose

Question 9

What does relative bioavailability determine?

Answer 9

formulation differences on drug absorption

Question 10

How is relative bioavailability obtained?

Answer 10

by comparing the AUC of the test and reference product.

Question 11

What is the criteria used for bioequivalence of relative bioavailability?

Answer 11

the ratio of the AUCs should be within 0.8-1.25

Question 12

Why are single dose studies preferred?

Answer 12

they can be completed in a shorter period of time

They involve less exposure of volunteer subjects to the drug

Question 13

Why are multiple dose or steady state studies used?

Answer 13

• When analytical methods are not sensitive enough after a single dose
• when studying controlled release products
• when studying a drug which is too toxic

Question 14

What is ka and ke?

Answer 14

ka = rate of absorption
ke = rate of elimination

Question 15

What would a curve look like if Ka> Ke?

Answer 15

Left skewed with peak near the start of time.

Question 16

How is a maximum point of drug content in the plasma reached?

Answer 16

Initially, as the drug is administered and plasma concentration increases, the rate of elimination will increase while the rate of absorption decreases. This is due to the concentration in the GIT decreasing (thus reducing the diffusion drive into cells)

The two rates will balance at a point which is the maximum plasma concentration.

Question 17

What happens at the start of a Ka>ke curve?

Answer 17

the rate for absorption is high because the concentration in the GIT is high.
The rate for elimination is low because the concentration in the plasma is low so there is an observable overall increase in plasma concentration

Question 18

What happens near the end of a ka>ke curve?

Answer 18

the rate of absorption nears 0 when the concentration in the GIT nears 0. Only elimination occurs and the rate of elimination is dependent on the existing plasma concentration

Question 19

What kinds of drugs would have ke>ka?

Answer 19

drugs with short biological half lives
drugs that exhibit prolonged absorption
drugs with a combination of the above

Question 20

What is onset?

Answer 20

the time required to achieve the minimum effective plasma concentration following administration of the dosage form

Question 21

What is duration?

Answer 21

the period during which the concentration of drug in plasma exceeds the minimum effective concentration

Question 22

What sort of kinetics does a single IV bolus dose follow?

Answer 22

first order kinetics, where if the data is plotted as a log of plasma conc. vs. time a straight line is formed.

Question 23

What are the characteristics of first order kinetics?

Answer 23

log plasma conc gives straight line
known as first order elimination
the drug concentration changes with respect to time as a function of the drug concentration remaining, and a first order rate constant .

rate = -kC where the negative indicates a decreasing tendency (as in the case of elimination)

Question 24

What is the elimination rate constant?

Answer 24

Concenration over a period of time = initial concentration x e^-kt

This is the fall in plasma drug concentration after a single dose

Question 25

What is half life?

Answer 25

the time taken for the amount of drug in the body (or plasma conc) to fall by a half.

k = 0.693/ t1/2

Question 26

How is half life related to elimination rate constant?

Answer 26

half life is a reciprocal function of the elimination rate constant

Question 27

What is Kel?

Answer 27

the terminal elimination rate constant or elimination half life

Question 28

what are some other PK parameters that may be explored in a BE study?

Answer 28

total urinary excretion

Question 29

What is an old method of calculating the area under the curve?

Answer 29

divide the area into triangles and trapeziums. calculate each individual area and add them together

Question 30

What is the area of a trapezium?

Answer 30

area = h(a+b)/2

Question 31

What is the area of a triangle?

Answer 31

area = (axb)/2

Question 32

How should the data be reported?

Answer 32

Two graphs to be drawn for each subject.
Two graphs to be drawn for the mean values of all subjects

Of these graphs, one should be linear and the other should be semi-logarithmic of the concentrations from the reference and test formulations against sampling times

Question 33

What is a semi logarithmic plot?

Answer 33

where plasma concentration axis is log-ed