Bioequivalence metrics for absorption rates: linearity, specificity, sensitivity

Vincze, István and Endrényi, László and Tóthfalusi, László (2019) Bioequivalence metrics for absorption rates: linearity, specificity, sensitivity. ACTA PHARMACEUTICA HUNGARICA, 89 (1). pp. 17-21. ISSN 0001-6659

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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: Ideally, 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.

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