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This ppt contains the basics notes of ba/be studies with sas outputs

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- 1. BIOEQUVALENCE AND BIOAVAILBILITY Manoj Kumar Pandey
- 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 .
- 7. Different
- 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.
- 13. Snap Shot of BA/BE With 2x2 Cross Over Design
- 14. Two way crossover design
- 15. Two way crossover design The BA/BE studies mostly conducted with standard two way crossover design for regulatory submission
- 16. stats Least Square Mean (LSM) Test - T Reference - R Geometric LSM* Test - T Reference - R LSM Difference (T - R) SE Difference p-value (Difference) Geometric LSM Ratio (%) Test - T / Reference - R (%) 90% Confidence Interval (%) Test - T vs. Reference - R Lower Confidence Limit Upper Confidence Limit Intra-Subject Variability (CV %) Inter-Subject Variability (CV %) Power (%) AUCT AUCI CMAX 2.9521 2.8817 3.0065 2.9486 0.547 0.5266 19.15 17.84 0.0705 0.081 0.3901 20.22 19.08 0.058 0.0778 0.4615 1.73 1.69 0.0204 0.0833 0.808 107.3 105.97 102.06 93.57 123.04 35.33 23.21 76.3 92.9 120.87 33.88 20.38 79.53 88.66 117.49 36.4 19.92 73.93
- 17. ANOVA Table source df ss ms fvalue probf Sequence 1 0.301686 0.301686 2.57 0.1185 Subject(Sequence) 34 7.567339 0.222569 1.89 0.0336 Period 1 0.013442 0.013442 0.11 0.7374 Treatment 1 0.089132 0.089132 0.76 0.3901 Residual 34 3.998678 0.117608 --------Sequence* 1 0.301686 0.301686 1.36 0.2524 Intra-Subject Variability (CV %) = 35.33 Inter-Subject Variability (CV %) = 23.21

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