Performance of Several Bioequivalence Metrics for Assessing the Rate and Extent of Absorption

Abstract

In this paper the problem of interest is the bioequivalence metrics and their role in assessing the rate and extent of absorption ratios of two drug formulations. Several bioequivalence metrics were proposed by several authors in the literature to estimate the similarity or dissimilarity of two drug formulations. The existing bioequivalence metrics are reviewed. A new bioequivalence metric is proposed and motivated. The performance, in terms of the statistical power, of the previously proposed and the new bioequivalence metrics is also evaluated by simulating cross-over bioequivalence trials.

A Bioequivalence Test by the Direct Comparison of Concentration-versus-Time Curves Using Local Polynomial Smoothers

“…Here, we used the PK model presented in [11] where the concentration function is represented by$\begin{array}{c}T1c\left(t\right)\propto \frac{K_a}{K_a-K_e}\left(e^{-k_{e}t}-e^{-k_{a}t}\right),\end{array}$where k a and k e are the absorption and the elimination rate constants. The concentration-versus-time curves for the reference drug and test drug were simulated as$\begin{array}{c}T17\log \left(Y_R\right)=\log \left(c\left(t\right)\right)+\epsilon ,\\ \\ \log \left(Y_T\right)=\log \left(c\left(t\right)\right)+\nabla +\epsilon ,\\ \\ \epsilon ~\text{MVN}\left({\mathrm{0}}_p,{\mathrm{\Sigma }}_{p\times p}\right),\end{array}$where the correlation between two measures, on the logarithm scale, from the same subject k   ( k = 1,2,…, 2 n ) was specified as a positive constant; that is, corr⁡( ε ik , ε jk ) = ρ   for   i ≠ j .…”

“…More importantly, when the confidence intervals of C max⁡ , T max⁡ , and AUC between two drugs all fall within the equivalence boundary (such that BE is concluded), it does not imply that the drugs are clinically equivalent since the overall shapes of the concentration-versus-time curves may in fact differ [11]. A falsely determined BE between two drugs when they are not clinically equivalent may be very harmful to the public.…”