This document defines bioavailability and bioequivalence and discusses related parameters and studies. It provides:
1) Definitions of bioavailability as the rate and extent to which the active drug is absorbed and available at the site of action, and bioequivalence as no significant difference in the rate and extent of absorption between test and reference drugs.
2) Reasons for conducting bioavailability/bioequivalence studies including changes to formulations, manufacturing processes, or for generic drug approval.
3) Key parameters analyzed in studies including Cmax, AUC, Tmax, and others to evaluate absorption rate and extent between test and reference drugs.
2. Definition Of Bioavailability (BA)
FDA Official statement (1997)
The rate and extent to which the active ingredient
of therapeutic moiety is absorbed from a drug
product and becomes available at the site of
action .
The
extent of bioavailability: AUC , Cmax
Rate of availability: Rate of availability: C Cmax
max, , T Tmax
3. Definition Of Bioequivalence (BE)
FDA Official statement (1997)
Two formulations are said to be bioequivalent if
″The rate and extent of absorption of the test drug do
not show a significant difference from the rate and
extent of absorption of the reference drug, when
administered at the same molar dose of the
therapeutic ingredient under similar experimental
conditions in either single dose or multiple doses ″
4. WHEN BA/BE STAUDIES DO
Clinical Service Form to Final Market Form
Change of formulations (capsules to tablet)
Generic Formulations
Change of Process or manufacturing site (some times)
5. BA/BE PARAMETERS
Following s are the BA/BE parameters
Cmax-This is the maximum drug concentration achieved in
systemic circulation following drug administration .
AUC0-t- Area under the plasma concentration – time curve
from 0 h to last sampling time.
AUC0-inf - Area under the plasma concentration – time curve
from 0 h to infinity time .
6. Contd..
Tmax-
It is the time required to achieve maximum drug
concentration in systemic circulation .
Kel
Thalf-
It is the time necessary to reduce the drug
concentration in blood ,plasma or serum to one-half after
equilibrium is reached .
8. Need for Conducting BA/BE Studies
BA
To evaluate the absolute systemic availability To active drug
substance from a dosage form
To
To
estimate the inter and intra subject variability
study the effect of food on bioavailability
9. Need for Conducting BA/BE Studies
BE
When significant changes are made in the manufacture of
the marketed
When a new generic formulation is tested against the
innovator ’s marketed product
10. Analysis of Data for Bioequivalence
Determination
Calculation of the natural log of the AUC and Cmax data The
FDA advocates logarithmically transforming AUC and Cmax
data prior to analysis.
Calculation of the difference between the transformed data for
each metric for each subject
The transformed value of the reference AUC is subtracted
from the transformed value of the test AUC for each patient.
This procedure is repeated for the transformed Cmax values.
Calculation of the mean difference between the trans-formed
data.
11. Contd..
Calculation of the standard deviation of the difference
between the transformed data.
Calculation of the P value of Difference
Calculation of the high and low bounds of confidence intervals
about the mean difference of the transformed data.
Calculation of the intra subject and inter subject variability.
Power calculation .
12. Decision rule
Bioequivalence is concluded if the confidence intervals about
the ratio of AUC and Cmax both fall within the range of 0.81.25. That is the lower bounds of the confidence intervals must
be greater than or equal to 0.8 and the upper bounds of the
confidence intervals must be less than or equal to 1.25. In the
present example, bioequivalence is not concluded as the lower
bound of each confidence interval is less than 0.8.
