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Analytes of Interest and Choice of Dose: Two Important Considerations in the Design of Bioequivalence Studies with Atorvastatin

Kuan Gandelman, Bimal Malhotra, Robert R. LaBadie, Penelope Crownover and Tamie Bergstrom

Atorvastatin is an oral lipid-lowering agent. A Small Tablet (ST) formulation and a Chewable Tablet (CT) formulation have recently been developed and tested in two single-dose bioequivalent (BE) studies (10 mg and 80 mg), each in 76 healthy volunteers. Plasma samples were only analyzed for atorvastatin in ST studies, and simultaneously for both atorvastatin and ortho-hydroxyatorvastatin in CT studies. The results showed the ST and the CT formulations were each bioequivalent to the current Marketed Tablet (MT) formulation, at the lowest (10 mg) and the highest (80 mg) doses. For the CT formulation, both atorvastatin and its metabolite achieved BE at both doses. Although the metabolite BE is not warranted, supportive metabolite data may be needed depending on the degree of divergence in formulations from its MT formulation. Furthermore atorvastatin has linear PK with respect to AUC; however, Cmax is nonlinear with a greater than dose-proportional increase. Therefore, to ensure the desired sensitivity to detect formulation differences, BE studies with atorvastatin should be conducted at the highest dose.