Comparison of pharmacokinetics of a fixed-dose combination of atorvastatin/ezetimibe 5 mg/10 mg versus separate tablets in healthy subjects

Abstract

The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are well-established treatment options for dyslipidemia. For patients not meeting low-density lipoprotein cholesterol targets with monotherapy, combination therapy with another lipid-lowering agent including ezetimibe, is recommended. This study compared the pharmacokinetics (PKs) and safety of a fixed-dose combination (FDC) of atorvastatin/ezetimibe 5 mg/10 mg with the individual components in healthy Korean subjects. A randomized, open-label, single-dose, 2-treatment, 2-sequence, crossover study was conducted in 60 healthy subjects. An FDC of atorvastatin/ezetimibe 5 mg/10 mg or the corresponding individual components was administered in the first period, and the alternative in the second period after a 14-day washout. Serial blood samples were collected up to 72 hours post-dose to calculate PK parameters such as maximum plasma concentration (C_max) and the area under the plasma concentration-time curve to the last measurable concentration (AUC_last). The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the C_max and AUC_last for the atorvastatin and total ezetimibe were estimated compared to the individual components. Adverse events (AEs) and other safety variables were monitored to evaluate safety and tolerability profile. Sixty subjects were enrolled and 58 subjects completed the study. For atorvastatin, the GMRs (90% CIs) for C_max and AUC_last were 1.18 (1.04-1.33) and 1.04 (1.00-1.08), respectively, and the corresponding values were 1.37 (1.26-1.50) and 0.98 (0.93-1.03) for total ezetimibe. No clinically significant treatment-emergent AEs were observed with either formulations. The FDC of atorvastatin/ezetimibe 5 mg/10 mg was safe and showed similar exposure to those of the individual components.

Trial registration: ClinicalTrials.gov Identifier: NCT05202405.

Keywords: Atorvastatin; Drug Combinations; Dyslipidemia; Ezetimibe; Pharmacokinetics.

Figure 1. Mean plasma concentration-time profiles of atorvastatin after a single oral administration of FDC formulation of atorvastatin/ezetimibe 5 mg/10 mg or concomitant administration of individual components of atorvastatin 5 mg and ezetimibe 10 mg in (A) linear scale and (B) log scale.

FDC, fixed-dose combination.

Figure 2. Mean plasma concentration-time profiles of total ezetimibe after a single oral administration of FDC formulation of atorvastatin/ezetimibe 5 mg/10 mg or concomitant administration of individual components of atorvastatin 5 mg and ezetimibe 10 mg in (A) linear scale and (B) log scale.

FDC, fixed-dose combination.

Figure 3. Mean plasma concentration-time profiles of free ezetimibe after a single oral administration of FDC formulation of atorvastatin/ezetimibe 5 mg/10 mg or concomitant administration of individual components of atorvastatin 5 mg and ezetimibe 10 mg in (A) linear scale and (B) log scale.

FDC, fixed-dose combination.