Sensitivity of empirical metrics of rate of absorption in bioequivalence studies

Purpose. The sensitivity and effectiveness of indirect metrics proposed for the assessment of comparative absorption rates in bioequivalence studies [ C-max, T-max, partial AUC (AUC(p)), feathered slops (SLf), intercept metric (1)] were originally tested by assuming first-order absorption. The presen t study re-evaluates their sensitivity performances using the more realisti c inverse Gaussian (IG) model characterizing the input process for oral dru g administration. Methods, Simulations were performed for both the first-order or exponential model (EX) which is determined by only one parameter, the mean absorption time (MAT = l/k(d)), anti the IG model, which additionally contains a shape parameter, the relative dispersion of absorption time distribution (CVA2). Kinetic sensitivities (KS) of the indirect metrics were evaluated from bio equivalence trials terror free data) generated with various ratios of the t rue parameters (MAT and CVA2) of the two formulations. Results. The behavior of the metrics was similar with respect to changes in MAT ratios with both models: KS was low with C-max, moderate with SLt and AUC(p), and high with I and T-max following correction for apparent lag tim e (T-lag). Changes of the shape parameter CVA2, however, were not detectabl e by C-max T-max, SLf, and AUC(p). Changes in both MAT and CVA2 were well r eflected by I with CVA2 - ratio > 1. I exhibited approximately full KS also with CVA2 -ratio < 1 when a correction was first applied for the apparent lag time. Conclusions, The time profile of absorption rates is insufficiently charact erized by only one parameter (MAT). Indirect metrics which are sensitive en ough to detect changes in the scale and shape of the input profile could be useful for bioequivalence testing. Among the tested measures, I is particu larly promising when a correction is applied for T-lag.