Open questions on bioequivalence: the case of cholecalciferol

Abstract

Cholecalciferol or vitamin D3 is an endogenous substance with the typical problems of bioavailability/bioequivalence of this class of substances. A previous trial has shown that, if administered orally at a dose of 800-10,000 IU and bioassayed as its 25-hydroxy metabolite, a slow absorption without an evident peak shape can be expected. However, if administered orally at a dose of 100,000-300,000 IU, this drug shows a well-defined peak shape of its metabolite 25-hydroxyvitamin D3 (which is exceptionally long-lasting) with time to peak (tmax) at seven days and a kinetic profile requiring 84 days or more to restore predose base-line levels. A recent paper has described a new bioassay of cholecalciferol in serum with a serum concentration-time curve after oral administration of 70 μg (2800 IU). An evident peak shape with Cmax of approximately 4 ng/mL was achieved at 12-24 h after administration. Baseline was restored after 96 h. However, these pharmacokinetic data were obtained in only one subject. This approach for bioassay of the parent drug seems to be more suitable for bioequivalence trials of cholecalciferol, even if more data concerning application are needed to adequately prepare a bioequivalence protocol. Therefore, the case of cholecalciferol appears to be extremely complex and remains one of the unanswered questions concerning bioequivalence that has not been taken into consideration in operating guidelines.

Keywords

• cholecalciferol, pharmacokinetics, bioequivalence, biowaiver.