Pharmacokinetic Comparison of a Fixed-Dose Combination of Candesartan Cilexetil/Amlodipine/Atorvastatin Versus Co-administration of Individual Formulations in Healthy Participants

Abstract

Introduction: Fixed-dose combinations (FDCs) of angiotensin II receptor blockers, calcium channel blockers, and statins are conventional therapeutic interventions prescribed for cardiovascular diseases. This study aimed at drawing a comparison between the pharmacokinetics and safety of an FDC and the corresponding individual formulations in healthy subjects. Methods: A randomized, open-label, single-dose, three-sequence, three-period, partially repeated crossover study was conducted with a cohort of healthy volunteers. A 14-day washout period was maintained between each of the three periods. In this study, candesartan cilexetil, amlodipine, and atorvastatin was administered orally as FDCs of 16/10/40 mg in study 1 and 16/5/20 mg in study 2. The maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from time zero to the time of the last quantifiable concentration (AUClast) of candesartan, amlodipine, and atorvastatin were estimated as the geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the FDC to individual formulations. If the within-subject coefficient of variation (CVwr) of Cmax was greater than 0.3, the bioequivalence (BE) range calculated using the reference-scaled average bioequivalence was used to assess whether the 90% CI was within the BE range. Results: The GMRs (90% CIs) for the AUClast for candesartan and amlodipine were 0.9612 (0.9158–1.0089)/0.9965 (0.9550–1.0397) and 1.0033 (0.9800–1.0271)/1.0067 (0.9798–1.0344), and the GMRs (90% CIs) for Cmax were 0.9600 (0.8953–1.0294)/0.9851 (0.9368–1.0359) and 1.0198 (0.9950–1.0453)/1.0003 (0.9694–1.0321) in studies 1 and 2, respectively. The extended BE ranges calculated from the CVwr of the Cmax of atorvastatin were 0.7814–1.2797 and 0.7415–1.3485, respectively. The GMRs (90% CIs) for the AUClast of atorvastatin were 1.0532 (1.0082–1.1003)/1.0252 (0.9841–1.0680), and the GMRs (90% CIs) for Cmax were 1.0630 (0.9418–1.1997)/0.9888 (0.8792–1.1120) in studies 1 and 2, respectively. Conclusion: The Cmax and AUClast values of candesartan cilexetil/amlodipine/atorvastatin 16/10/40 mg and 16/5/20 mg, respectively, were within the BE ranges. There were no clinically significant differences in safety between the two formulations. Trial Registration: ClinicalTrials.gov identifier, study 1: NCT04478097; study 2: NCT04627207.