Bioequivalence of endogenous substances facing homeostatic equilibria: An example with potassium

Oral administration of endogenous substances in most cases results in negli gible net increases in baseline plasma concentrations, associated with high variability. This poses the problem of their bioequivalence. Using the dat a obtained from a bioequivalence investigation of potassium aspartate (test vs reference formulation), the authors demonstrate the inconsistency of bi oequivalence based on plasma concentrations and standard methods. Potassium aspartate was given orally at a dose of 15.8 mmoles to 12 healthy volunteers as test and reference values according to a two-period, two-for mulation, two-sequence design. The individual net values of the area under the curve of plasma concentration (AUC) and cumulative urinary excretion (C UE), both obtained with the test formulation as post-dose minus baseline, w ere multiplied by 2, 3, 4, 5 and 6 and added to the baseline in order to si mulate the administration of increasing single doses of the test, assuming dose-linear kinetics. Data generated with the test formulation were compare d with original data of the reference according to 90% confidence intervals . With AUG, bioequivalence of test and reference formulations was demonstrate d with 1 : 1, 2 : 1 and 3 : 1 test to reference dose ratios. With CUE only the 1:1 dose ratio comparison produced bioequivalence. The authors conclude that bioequivalence of endogenous substances conducted with standard procedures in most cases is a useless exercise. With potassi um and more generally with drugs cleared via urine, urinary excretion would reflect the extent of absorption more faithfully than AUG. (C) 2000 Academ ic Press.