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Pharmacokinetic and Safety Profiles of a Fixed‐Dose Combination of Amlodipine, Valsartan, and Atorvastatin: A 3‐Period Replicate Crossover Study
Author(s) -
Kim Seokuee,
Ko JaeWook,
Kim JungRyul
Publication year - 2020
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.727
Subject(s) - atorvastatin , bioequivalence , valsartan , amlodipine , crossover study , medicine , pharmacokinetics , pharmacology , confidence interval , mathematics , placebo , blood pressure , alternative medicine , pathology
The objective of study was to compare the pharmacokinetic and safety profiles of a fixed‐dose combination (FDC) formulation of 5/160/20 mg amlodipine/valsartan/atorvastatin with those of separate formulations of a 5/160‐mg amlodipine/valsartan tablet and a 20‐mg atorvastatin tablet. This was a randomized, open‐label, single‐dose, 3‐sequence, 3‐period replicate crossover study with 42 subjects. Serial blood samples for pharmacokinetic assessment were collected up to 72 hours postdose. For establishing bioequivalence (BE) for amlodipine, valsartan, and atorvastatin, a reference‐scaled average BE approach was used if applicable, as well as the conventional limit of 0.80‐1.25. The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) for the maximum plasma concentration (C max ) and the area under the curve to the last measurable concentration (AUC t ) between the FDC and separate formulations were within the 0.80‐1.25 limit for all analytes but atorvastatin. The estimated within‐subject standard deviation of the log‐transformed values of the separate formulations, the reference intervention, was 0.3804 for the C max of atorvastatin, being set at 0.7489‐1.3352 for the BE acceptance limit. For both the C max and AUC t for atorvastatin, the GMRs lay within 0.80‐1.25, and the 90%CIs for the GMRs were within the BE acceptance limit. This 3‐period replicate crossover study demonstrated the BE of the FDC formulation of amlodipine, valsartan, and atorvastatin and the separate formulations of an amlodipine/valsartan tablet and an atorvastatin tablet. A similar incidence of treatment‐emergent adverse events (TEAEs) was observed in both interventions, and headache was the most common TEAE.