Comparison of the Pharmacokinetics of Highly Variable Drugs in Healthy Subjects Using a Partial Replicated Crossover Study: A Fixed-Dose Combination of Fimasartan 120 mg and Atorvastatin 40 mg versus Separate Tablets.

ABSTRACT

PURPOSE: A fixed-dose combination (FDC) of fimasartan and atorvastatin is used to treat hypertension and dyslipidemia. The peak plasma concentration (Cmax) of fimasartan and atorvastatin has a large intra-subject variability with a maximum coefficient of variation of 65% and 48%, respectively. Therefore, both drugs are classified as highly variable drugs. The purpose of this study was to compare the pharmacokinetics (PK) between a FDC of fimasartan 120 mg and atorvastatin 40 mg versus separate tablets in healthy male Korean subjects. SUBJECTS AND METHODS: A randomized, single-dose, two-treatment, three-sequence, three-period, partial replicated crossover study was conducted with a 7-day washout interval between periods. Blood samples for fimasartan and atorvastatin were collected until 48 hours after administration in each period. PK parameters were calculated using the non-compartmental method. Geometric mean ratios (GMRs) for PK parameters of FDC to loose combination and their 90% confidence intervals (90% CIs) were estimated. RESULTS: A total of 56 subjects completed the study. GMRs (90% CIs) of the Cmax for fimasartan and atorvastatin were 1.08 (0.93-1.24) and 1.02 (0.92-1.13), respectively. The expanded 90% CIs of both drugs using the intra-subject variability was calculated range of 0.70-1.43 and 0.73-1.38, respectively. The corresponding values of area under the concentration-time curve from zero to the last measurable time point were 1.02 (0.97-1.08) and 1.02 (0.98-1.07), respectively. CONCLUSION: FDC of fimasartan 120 mg and atorvastatin 40 mg between their loose combination showed similar PK characteristics.