Pharmacokinetic Interaction Among Amlodipine, Losartan, and Chlorthalidone after a Single Oral Administration in Healthy Male Subjects

Antihypertensive drugs are more potent when administered in combinations of two or three different classes of drugs. The objective of this study was to evaluate the pharmacokinetic interaction among amlodipine, losartan, and chlorthalidone. A randomized, open-label, four-sequence, four-period, four-treatment, single-dose study was conducted in healthy Korean male subjects, with oral administrations of two tablets of amlodipine 5 mg, one tablet of losartan 100 mg, one tablet of chlorthalidone 25 mg, or co-administration of all three investigational products. Plasma drug concentrations were measured by liquid chromatography/tandem mass spectrometry. Twenty-six subjects completed the study. The geometric mean ratios and 90% confidence intervals of C_max and AUC_last, respectively, were 1.0928 (1.0412-1.1469) and 1.0360 (0.9958-1.0778) for amlodipine; 1.1016 (0.9136-1.3284) and 1.1606 (1.0885-1.2375) for losartan; 1.0720 (1.0119-1.1356) and 1.0902 (1.0350-1.1148) for EXP3174 (active metabolite of losartan); and 0.9462 (0.8626-1.0379) and 1.0266 (0.9752-1.0807) for chlorthalidone. All the treatments were well tolerated overall. Besides the slight increase in losartan C_max, the combination therapy did not show clinically significant pharmacokinetic interactions in terms of systemic drug exposure.