Phase 1 Evaluation of the Bioequivalence and Drug‐Drug Interaction Potential of a Novel Fixed‐Dose Combination of Ezetimibe, Atorvastatin, and Amlodipine

Abstract A fixed‐dose combination (FDC) of ezetimibe, atorvastatin, and amlodipine has been developed to improve medication adherence among patients with cardiovascular diseases. In a randomized, open‐label, multiple‐dose, fixed‐sequence study involving 34 participants (Study 1), the potential drug‐drug interaction between ezetimibe/atorvastatin FDC and amlodipine was evaluated. Additionally, a randomized, open‐label, crossover study with 60 participants (Study 2) compared the pharmacokinetics (PKs) of ezetimibe/atorvastatin/amlodipine FDC to those of individual formulations. Co‐administration of the ezetimibe/atorvastatin FDC and amlodipine did not significantly alter the PKs of either drug. However, amlodipine resulted in a slight increase in systemic exposure to atorvastatin by approximately 23%. Geometric mean ratios (FDC to individual formulations) and 90% confidence intervals of area under the time‐concentration curve at steady state during dosing interval (AUC τ, ss ) and maximum concentration at steady state (C max, ss ) or amlodipine, atorvastatin, and ezetimibe were all within the bioequivalent range (0.8‐1.25), confirming bioequivalence. Moreover, the FDC of ezetimibe, atorvastatin, and amlodipine exhibited comparable tolerability to corresponding individual formulations.