Bioequivalence metrics for absorption rates: linearity, specificity, sensitivity

Abstract

Aims:In order to ensure the therapeutic equivalence of generic products, it would be important to contrast measures additional to Cmax in order to assess differences in absorption rates. Our aim was to compare partial AUC (PAUC), Swing, and PTF to Cmax in terms of sensitivity, specificity and linearity under identical kinetic conditions.
 Methods:Single-dose and multiple-dose concentration curves were generated assuming one-compartment models. Kinetic sensitivity curves were obtained by gradually changing the absorption rate constant and keeping all other parameters fixed.
 Results:A metric should reflect specifically the investigated kinetic feature (e.g., the rate of absorption), be linearly related to it, and should exhibit high kinetic sensitivity. Cmax is related nonlinearly to the rate of absorption, is nonspecific to it (reflects also the extent of absorption as well as the rates of disposition processes), lacks kinetic sensitivity even following a single administration. Compared to Cmax, PAUC was always more sensitive under every investigated condition. Swing and PTF showed high kinetic sensitivity but, in contrast to PAUC, they could be evaluated only in multiple-dose studies. 
 Conclusion:Under identical conditions, different metrics provide widely differing point estimates. Differences in kinetic sensitivity among bioequivalence metrics should be accounted for when results of different metrics are compared.

An In Silico Approach toward the Appropriate Absorption Rate Metric in Bioequivalence

“…The findings regarding kinetic sensitivity found in this study are in agreement with the study of Vincze et al, who studied the kinetic sensitivities of Cmax and partial AUCs under single and multiple administration [27]. It was shown that Cmax was less sensitive even when compared to partial areas.…”

“…The analysis continued with the investigation of the kinetic sensitivity of all metrics. If a change in one of the examined kinetic parameters results in an equivalent change in the measured metric, the latter is said to have full kinetic sensitivity [ 27 ]. With regard to the rate of absorption, full kinetic sensitivity would prevail if, for example, a 25% change in the latter would result in a 25% change in the absorption rate metric.…”

“…With regard to the rate of absorption, full kinetic sensitivity would prevail if, for example, a 25% change in the latter would result in a 25% change in the absorption rate metric. If, however, a change in the parameter produces a considerably smaller change in the metric, the metric lacks full kinetic sensitivity to the parameter [ 27 ]. In this study, this investigation task was achieved by applying a Monte Carlo pharmacokinetic–bioequivalence simulation approach.…”