Sensitivity of Empirical Metrics of Rate of Absorption in Bioequivalence Studies

Purpose. The sensitivity and effectiveness of indirect metrics proposedfor the assessment of comparative absorption rates in bioequivalencestudies [C_max, T_max, partial AUC(AUC_p), feathered slope (SL_f), interceptmetric (I)] were originally tested by assuming first-order absorption.The present study re-evaluates their sensitivity performances using themore realistic inverse Gaussian (IG) model characterizing the inputprocess for oral drug administration.Methods. Simulations were performed for both the first-order orexponential model (EX) which is determined by only one parameter, themean absorption time (MAT = 1/k_a), and the IG model, whichadditionally contains a shape parameter, the relative dispersion of absorptiontime distribution (CV²_A). Kinetic sensitivities (KS) of the indirectmetrics were evaluated from bioequivalence trials (error free data)generated with various ratios of the true parameters (MAT and CV²_A) of thetwo formulations.Results. The behavior of the metrics was similar with respect tochanges in MAT ratios with both models: KS was low with C_max,moderate with SL_f and AUC_p, and high with I and T_max followingcorrection for apparent lag time (T_lag). Changes of the shape parameterCV²_A, however, were not detectable by C_max, T_max, SL_f, and AUC_p.Changes in both MAT and CV²_A were well reflected by I with CV²_A - ratio> 1. I exhibited approximately full KS also with CV²_A - ratio <1 when a correction was first applied for the apparent lag time.Conclusions. The time profile of absorption rates is insufficientlycharacterized by only one parameter (MAT). Indirect metrics which aresensitive enough to detect changes in the scale and shape of the inputprofile could be useful for bioequivalence testing. Among the testedmeasures, I is particularly promising when a correction is appliedfor T_lag.