Definition of individual bioequivalence: occasion-to-occasion versus mean switchability.
Two moment-based scaled definitions of individual bioequivalence are discussed. Based on a mixed effects linear model, their evaluations respectively lead to an unweighted (theta(11)) and a parametric (theta(15)) metric. The two metrics are estimated with respect to study design and two estimation methods. Results show that the two IBE metrics perform equivalently in the fully replicated design. In the semi-replicated design, the definition of theta(11) may not be valid while the evaluation of theta(15) results in a reduction of the weights in the mean difference and switchability components of the metric. Percentage rejection rates in the latter design indicate that theta(11) is more conservative than theta(15). This is because there is an increase of about 15 per cent in the producer risk in theta(11) relative to theta(15) compared to a 7 per cent increase in the consumer risk in theta(15) relative to theta(11). A further disadvantage of the design is that there is a 33 per cent loss in the subject-by-treatment variance efficiency which is reflected in a similar amount of decreased sensitivity to departures from perfect bioequivalence even when more subjects are used to equalize the number of exposure occasions in the two designs. It is concluded that a mean switchability criterion may be more appropriate from an interpretability perspective, the bootstrap resampling method used to evaluate individual bioequivalence based on theta(11) may need to be bias-corrected and that the semi-replicated design should be used cautiously.
Kimanani
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Biometrics and Pharmacokinetics R&D, Phoenix International Life Sciences, 2350 Cohen Street, Ville Saint-Laurent, QC, H4R 2N6, Canada.
D006801:Humans; D015233:Models, Statistical; D012107:Research Design; D009626:Terminology as Topic; D013810:Therapeutic Equivalency