The purpose of this study is to evaluate the comparative bioavailability of two fixed dose combination tablet formulations of amlodipine and losartan in healthy volunteers. Subjects will receive each of the following three treatments administered in a randomized three-way crossover design: a reference treatment consisting of a 5mg amlodipine tablet and 100mg losartan tablet; a fixed dose combination tablet consisting of 5mg amlodipine and 100mg losartan; and another fixed dose combination tablet consisting of 5mg amlodipine and 100mg losartan; all three treatments will be administered once orally and in a fasted state. Serial blood samples will be obtained at pre-defined timepoints for pharmacokinetic analysis of amlodipine, losartan and carboxylic acid (this is the primary active losartan metabolite). Safety assessments will include measurements of orthostatic vital signs, electrocardiograms (ECG), collection of adverse events (AE) and clinical laboratory tests.
Amlodipine and losartan are calcium channel and angiotensin II receptor type-1 blockers, respectively, and are established treatments to manage blood pressure (BP) levels for patients with hypertension; both medications are currently marketed in the United States and Europe as anti-hypertensive agents. This is a an open-label, randomized, single dose, three-way crossover study enrolling 24 healthy adult male and female subjects under fasting conditions. Each subject will participate in three treatment periods. The study consists of a screening phase, three treatment periods and a follow-up visit. Subjects will receive each of the following three treatments administered in a randomized three-way crossover design: a reference treatment consisting of a single 5mg amlodipine tablet and a single 100mg losartan tablet; a single fixed dose combination tablet consisting of 5mg amlodipine and 100mg losartan; and another single fixed dose combination tablet consisting of 5mg amlodipine and 100mg losartan; all three treatments will be administered once orally and in a fasted state. Serial blood samples will be obtained at pre-defined timepoints for pharmacokinetic analysis of amlodipine, losartan and carboxylic acid (this is the primary active losartan metabolite). Safety assessments will include measurements of orthostatic vital signs, electrocardiograms (ECG), collection of adverse events (AE) and clinical laboratory tests.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
23
1 x 5mg amlodipine tablet and 1 x 100mg losartan tablet administered in fasted state
1 x 5mg amlodipine / 100mg losartan tablet administered in fasted state
1 x 5mg amlodipine / 100mg losartan tablet administered in fasted state
GSK Investigational Site
Randwick, New South Wales, Australia
Plasma concentration of amlodipine and losartan: Peak plasma concentration (Cmax) and last measurable plasma concentration (Clast)
Comparison of Cmax and Clast after administration of two amlodipine and losartan fixed dose combinations in comparison to reference treatment (to determine the comparative bioavailability)
Time frame: Participants will be followed and monitored for the duration of their hospital stay (24 hours per treatment period). The longest duration of participation in the study will be approximately 14 weeks
Time to peak plasma concentration (Tmax) of amlodipine and losartan
Comparison of Tmax after administration of two amlodipine and losartan fixed dose combinations in comparison to reference treatment (to determine the comparative bioavailability)
Time frame: Participants will be followed and monitored for the duration of their hospital stay (24 hours per treatment period). The longest duration of participation in the study will be approximately 14 weeks
Area under the plasma concentration-time curve (AUC) of amlodipine and losartan: from time zero to time t (AUCt), from time zero to infinity (AUCinf) and time t to infinity as a percentage of total AUC (%AUCex)
Comparison of AUCt, AUCinf and %AUCex after administration of two amlodipine and losartan fixed dose combinations in comparison to reference treatment (to determine the comparative bioavailability)
Time frame: Participants will be followed and monitored for the duration of their hospital stay (24 hours per treatment period). The longest duration of participation in the study will be approximately 14 weeks
Elimination half-life (t½) of amlodipine and losartan
Comparison of t½ after administration of two amlodipine and losartan fixed dose combinations in comparison to reference treatment (to determine the comparative bioavailability)
Time frame: Participants will be followed and monitored for the duration of their hospital stay (24 hours per treatment period). The longest duration of participation in the study will be approximately 14 weeks
Number of healthy volunteers with adverse events
Comparison of adverse events (as determined by orthostatic vital sign and electrocardiogram measurements and clinical lab results) after administration of two amlodipine and losartan fixed dose combinations in comparison to reference treatment (to determine the safety and tolerability)
Time frame: Participants will be followed and monitored for the duration of their hospital stay (24 hours per treatment period). The longest duration of participation in the study will be approximately 14 weeks
Plasma concentration of of carboxylic acid: Peak plasma concentration (Cmax)
Comparison of Cmax and Clast after administration of two amlodipine and losartan fixed dose combinations in comparison to reference treatment (to determine the comparative bioavailability)
Time frame: Participants will be followed and monitored for the duration of their hospital stay (24 hours per treatment period). The longest duration of participation in the study will be approximately 14 weeks
Elimination half-life (t½) of carboxylic acid
Comparison of t½ after administration of two amlodipine and losartan fixed dose combinations in comparison to reference treatment (to determine the comparative bioavailability)
Time frame: Participants will be followed and monitored for the duration of their hospital stay (24 hours per treatment period). The longest duration of participation in the study will be approximately 14 weeks
Time to peak plasma concentration (Tmax) of carboxylic acid
Comparison of Tmax after administration of two amlodipine and losartan fixed dose combinations in comparison to reference treatment (to determine the comparative bioavailability)
Time frame: Participants will be followed and monitored for the duration of their hospital stay (24 hours per treatment period). The longest duration of participation in the study will be approximately 14 weeks
Area under the plasma concentration-time curve (AUC) of carboxylic acid: from time zero to time t (AUCt), from time zero to infinity (AUCinf) and time t to infinity as a percentage of total AUC (%AUCex)
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Comparison of AUCt, AUCinf and %AUCex after administration of two amlodipine and losartan fixed dose combinations in comparison to reference treatment (to determine the comparative bioavailability)
Time frame: Participants will be followed and monitored for the duration of their hospital stay (24 hours per treatment period). The longest duration of participation in the study will be approximately 14 weeks