Bioequivalence of endogenous substances facing homeostatic equilibria: an example with potassium.
Oral administration of endogenous substances in most cases results in negligible net increases in baseline plasma concentrations, associated with high variability. This poses the problem of their bioequivalence. Using the data obtained from a bioequivalence investigation of potassium aspartate (test vs reference formulation), the authors demonstrate the inconsistency of bioequivalence 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-formulation, two-sequence design. The individual net values of the area under the curve of plasma concentration (AUC) and cumulative urinary excretion (CUE), both obtained with the test formulation as post-dose minus baseline, were multiplied by 2, 3, 4, 5 and 6 and added to the baseline in order to simulate the administration of increasing single doses of the test, assuming dose-linear kinetics. Data generated with the test formulation were compared with original data of the reference according to 90% confidence intervals. With AUC, bioequivalence of test and reference formulations was demonstrated 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 potassium and more generally with drugs cleared via urine, urinary excretion would reflect the extent of absorption more faithfully than AUC.
Marzo
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I.P.A.S. S.A., Institute for Pharmacokinetic and Analytical Studies, Via Mastri 36, 6853 Ligornetto, Switzerland. clinpharm@ipas-research.com
Vuksic
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Crivelli
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D000328:Adult; D019540:Area Under Curve; D001224:Aspartic Acid / Q000493:pharmacokinetics*; D006706:Homeostasis; D006801:Humans; D013810:Therapeutic Equivalency
D001224:Aspartic Acid