Scale effect in bioequivalence evaluations.
OBJECTIVE
The objective of the study was to evaluate the relationship between the magnitude of the sample means for a bioavailability measure and the ratio of the sample means in bioequivalence evaluations.


METHODS
We assumed that bioavailability data were obtained from crossover trials on a test and a reference drug products. The true test-reference ratio was constructed as a function of dosage strength under certain dose-response relationship assumptions, and was used for deriving analytical results of assessing the scale effect due to dosage strength. In addition, the test-reference ratio of sample means was constructed as a function of the true test-reference ratio and the correlated sampling deviation in the sample means, and was used in a deterministic simulation for quantifying the scale effect due to the correlated sampling deviation.


RESULTS
The major systematic factors that influence the magnitude of the sample means include the dosage strength, dose-response relationship, and the positively correlated sampling deviation in the sample means. RESULTS of this study showed that the true test-reference ratios can be improved with increasing dosage strength in most of the situations studied, but at a diminishing rate. The correlated sampling deviation can alter the test-reference ratio of the sample means through changing magnitude of the sample means, especially for drug products with low bioavailability.


CONCLUSIONS
For extended release drug products with multiple dosage strengths, the development efforts should focus on the lowest strength if there is little or no formulation by dose interaction effect. Pilot studies should be conducted for both the highest and the lowest strength instead for possible formulation by dose interaction effect. The magnitude of observed means for bioavailability measures on the reference drug product can indicate the degree of systematic variation in the ratio of means. The expected mean values of the reference drug product can be derived from previous trial(s) and/or from other information sources. If the sample mean for the reference drug product in a failed bioequivalence trial is lower than expected, the investigator should consider repeating the trial.
Wang
Y
Y
Research and Development Division, Biovail Corporation International, Mississauga, ON, Canada.
Eradiri
O
O
Odidi
I
I
Geng
W
W
Odidi
A
A
Muhuri
G
G
D000465:Algorithms; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D006801:Humans; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000592:standards*; D013810:Therapeutic Equivalency
D004364:Pharmaceutical Preparations