Pharmacokinetic non-interaction analysis in a fixed-dose formulation in combination of atorvastatin and ezetimibe

Abstract

Recent clinical research has shown that atorvastatin (ATO) in combination with cholesterol absorption inhibitor ezetimibe (EZE) significantly reduces LDL-C level in patients with hypercholesterolemia, showing a superior lipid-lowering efficacy compared to statin alone. With no information currently available on the interaction between the two drugs, a pharmacokinetic study was conducted to investigate the influence of EZE on ATO and conversely when the two drugs were coadministered. The purpose of this study was to investigate the presence of differences in the pharmacokinetic profiles of capsules containing ATO 80 mg, EZE 10 mg or the combination of both 80/10 mg administered to healthy Mexican volunteers. This was a randomized, three-period, six-sequences crossover study. 36 eligible subjects aged between 20 to 50 years were included. Blood samples were collected up to 96 h after dosing, and pharmacokinetic parameters were obtained by non-compartmental analysis. Adverse events were evaluated based on subject interviews and physical examinations. Area under the concentration-time curve (AUC) and maximum plasma drug concentration (Cmax) were measured for each drug alone or together and tested for bioequivalence-based hypothesis. The estimation computed (90% confidence intervals) for AUC and Cmax, were 96.04% (85.88-107.42%) and 97.04% (82.36-114.35%), respectively for ATO-EZE combination versus ATO alone, while 84.42% (77.19-92.32%) and 95.60% (82.43-110.88%), respectively, for ATO-EZE combination versus EZE alone were estimated. These results suggest that ATO and EZE have no relevant pharmacokinetic drug-drug interaction.

Keywords: LC-MS-MS; atorvastatin; ezetimibe; pharmacokinetic drug–drug interaction; statins.

FIGURE 1

Time-course of plasma levels of atorvastatin (80 mg) when given alone or in combination with 10 mg of ezetimibe in healthy subjects. (A) Arithmetic profile 025 h; (B) Semilogarithmic profile 025 h; (C) Arithmetic profile 012 h.

FIGURE 2

Time-course of plasma levels of ezetimibe (10 mg) when given alone or in combination with 80 mg of atorvastatin in healthy subjects. (A) Arithmetic profile 0–96 h; (B) Semilogarithmic profile 0–96 h; (C) Arithmetic profile 0–12 h.