Pharmacokinetic and Bioequivalence Study of the Two-component Drug Product "Ezetimibe + rosuvastatin" (JSC "Sanofi-aventis group", Russia): Resuts and Experience with the Use of Enzymatic Hydrolysis in the Analysis of Samples

Introduction. As a part of the registration of the drug product a bioequivalence study of the fixed-dose combination "Ezetimibe + rosuvastatin" (JSC "Sanofi-aventis group", Russia) compared with coadministered Ezetrol® (ezetimibe) and Crestor® (rosuvastatin) was conducted with 76 healthy volunteers. Enzymatic hydrolysis was used to evaluate the pharmacokinetics of total ezetimibe. This was the reason for the inclusion of the additional monitored parameters in the validation and analysis.

Aim. The purpose of the bioequivalence trial was a comparative study of the pharmacokinetics and evidence of the bioequivalence of the fixed-dose combination "Ezetimibe + rosuvastatin" (ezetimibe + rosuvastatin,tablets, 10 + 40 mg, JSC "Sanofi-aventis group", Russia) compared with coadministrated monocomponent drugs ezetimibe and rosuvastatin in fasting healthy volunteers after a single administration using the described additional parameters for controlling the enzymatic hydrolysis of ezetimibe-glucuronide during the analysis of samples.

Materials and methods. To prove bioequivalence, an open label, comparative, randomized, crossover two-period clinical trial was conducted. During the study, blood plasma samples were taken from volunteers, the concentrations of ezetimibe (unconjugated) and total ezetimibe (ezetimibe + ezetimibe-glucuronide) and rosuvastatin in plasma samples were determined by validated HPLC-MS/MS methods. Based on the received data pharmacokinetic and statistical analysis was performed and confidence intervals (CI) for the pharmacokinetic parameters C_max and AUC_0-72 were calculated.

Results and discussion. It can be concluded that the studied formulations are bioequivalent in terms of pharmacokinetic parameters of ezetimibe (free) and rosuvastatin. Pharmacokinetic parameters of total ezetimibe were considered as secondary and were not required for the conclusion on bioequivalence. While HPLC-MS/MS analysis of incurred samples, additional control parameters for the enzymatic hydrolysis of ezetimibe-glucuronide made it possible to legitimately reject the results of inaccurate analytical batches.

Conclusion. Thus, according to the criteria used in the study, the drugs are proved to be bioequivalent. The described additional parameters for controlling the enzymatic hydrolysis of ezetimibe-glucuronide have been shown to be effective.

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