Examining the Role of Metabolites in Bioequivalence Assessment

Abstract

-Purpsoe. Investigate the role of metabolites in bioequivalence (BE) assessment. Methods. Sets of ordinary differential equations are used to generate concentration -time data for both parent drug (P) and metabolite (M). The calculations include 24 subjects, two different formulations (Test, Reference), and a range of Test/Reference ratios for the fraction of dose absorbed and the rate of absorption. A summarized view of these results is made through the construction of three dimensional power curves. The criteria for the choice of the preferred analyte (P or M) are based on a sensitivity analysis of the bioequivalence measure (AUC, C max ). The latter depends on the relative ability of P and M to reflect better the changes of the pharmacokinetic parameters and variability. Results. The different sensitivity properties of P and M were reflected on the power curves. For AUC, the performance of metabolite is very similar to that of the parent drug for all scenarios and models examined. A more complex behaviour is evident for C max . In most of these cases, metabolite data show higher permissiveness in the percentages of acceptance. This attribute is more evident when P exhibits high elimination rate and/or the formation of M occurs rapidly. When the Test and Reference products have similar absorption profiles, metabolite data are preferable for the determination of bioequivalence. Parent drug has the advantage for detecting better the differences in the absorption rate of two drugs. The latter is counterbalanced by the increased sensitivity of P data to the variability of the data. Conclusions. Both parent drug and metabolite share the same ability to declare BE when AUC is used as a bioequivalence measure. In case of C max , metabolite data exhibit better performance when the T and R products are truly bioequivalent or the two formulations differ in their extent of absorption. For the pharmacokinetic scenarios studied, parent drug data were found to be more sensitive to detect differences in the rate of absorption. However, in such cases, their information is much influenced by the increased variability. _______________________________________________________________________________________

Significance of Metabolites in Bioequivalence: Losartan Potassium as a Case Study

“…However, when the ratio of the absorption rate constants ( k aT / k aR ) was used, a complex behavior was observed with C max of the parent drug showing more sensitivity in detecting the difference in the absorption rate. Although the parent drug was more sensitive to detect the difference in the rate of absorption, but increased variability associated with it influenced the data . Further, such differences in the absorption rate detected by the parent compound might not be clinically relevant, especially in case of therapies for chronic ailments.…”

FDA Bioequivalence Standards

“…Simulations were conducted to evaluate the role of metabolites in BE assessment by various groups. Although different models and assumptions were used, a general conclusion was drawn from different groups (Braddy and Jackson 2010;Chen and Jackson 1991;Jackson 2000;Fernandez-Teruel et al 2009a, b;Karalis and Macheras 2010;Navarro-Fontestad et al 2010) that the parent drug is more sensitive to detect the difference in the rate of absorption which reflects the differences in formulation. BE simulations were also involved in the selection of single-dose (SD) vs. multiple-dose (MD) design.…”

Bioequivalence studies in Europe before and after 2010

“…Measurement of metabolite concentrations in plasma in order to establish BE is an issue that has been under discussion for more than two decades and certain specific recommendations have been proposed (72)(73)(74)(75)(76). Before the EMA 2010 guideline, a set of cases were defined where the measurement of the active or inactive metabolite was preferred compared to the parent compound (2,12).…”

“…Simulations studies published in the literature triggered or served as the basis for clarifying or setting several issues in the regulatory guidelines. The use of simulation studies in BE assessment includes several aspects like the choice of the suitable PK metrics for expressing extent and rate of absorption, the statistical assessment procedure, the role of metabolites, the introduction of scaled BE approaches, and the more recent two-stage designs (25)(26)(27)(28)(29)(30)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(58)(59)(60)(61)(62)(63)(64)(65)(66)(72)(73)(74)(75)(76)(77)(127)(128)(129)(130)(131)(132).…”