Abstract
Since angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists have complimentary mechanisms of action, enalapril, an ACE inhibitor, is used in combination with felodipine, a vascular selective dihydropyridine calcium antagonist, for the treatment of hypertension. The present study was designed to investigate the possible drug-drug interaction between these two agents in Chinese healthy subjects. A randomized, open-label, multiple-dose, 3-treatment, 3-period, 6-sequence cross-over study enrolling 12 healthy subjects (six male and six female subjects) was performed. Plasma pharmacokinetic studies were performed after 5 mg of enalapril and 5 mg of felodipine were administered alone or concomitantly twice per day for six days, and once in the morning of day seven. All 12 healthy subjects (mean [SD] age, 24.3 [2.8] years; body weight, 57.3 [5.7] kg; height, 163.2 [5.2] cm) completed all scheduled pharmacokinetic studies. Geometric mean ratios (with 90% CIs) of AUCτ,ss and Cmax,ss for enalapril administered concomitantly with felodipine vs. enalapril administered alone were 1.025 (0.80-1.25) and 1.065 (0.70-1.43), respectively. Geometric mean ratios (with 90% CIs) of AUCτ,ss and Cmax,ss for felodipine administered concomitantly with enalapril vs. felodipine administered alone were 1.14 (0.97-1.31) and 0.80 (0.65-0.95), respectively. There were no severe or serious drug-related adverse events observed during the study. Our results revealed that the co-administration of enalapril and felodipine affected the pharmacokinetics of felodipine, but not that of enalapril. Although the difference in PK parameters was statistically significant, its clinical significance may be limited, considering safety profile observed in the present study.
Highlights
The traditional stepwise standard care of hypertension includes the initial step of selecting a single drug, and if necessary, titrating its dosage upward to reach the treatment goal
Plasma pharmacokinetic studies were performed after 5 mg of enalapril and 5 mg of felodipine were administered alone or concomitantly twice per day for six days, and once in the morning of day seven
Our results revealed that the coadministration of enalapril and felodipine affected the pharmacokinetics of felodipine, but not that of enalapril
Summary
The traditional stepwise standard care of hypertension includes the initial step of selecting a single drug, and if necessary, titrating its dosage upward to reach the treatment goal. Additional drugs may be added only if blood pressure (BP) control cannot be achieved with a single agent [1, 2]. It has increasingly been recognized that the upward dose titration of antihypertensive agents can result in a significant increase in side effects with little additional effect on BP control [3,4,5]. It has been advocated that combination therapy with low doses of multiple agents can be an alternative strategy for better achieving BP control with fewer adverse effects [6,7,8,9]. Induced edema is not related to fluid retention, but to arteriolar dilation, resulting in an increase in capillary hydrostatic pressure that causes a fluid shift from circulation into the surrounding tissues. Enalapril can reduce capillary pressure and the extravasation of fluid into interstitial spaces [13]
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