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Pharmacokinetics and Pharmacodynamics of Irbesartan in Healthy Subjects
Author(s) -
Marino Maria R.,
Langenbacher Kathleen,
Ford Neville F.,
Uderman Howard D.
Publication year - 1998
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1998.tb04422.x
Subject(s) - irbesartan , pharmacokinetics , medicine , placebo , pharmacodynamics , plasma renin activity , angiotensin ii , pharmacology , area under the curve , dose , dose–response relationship , urology , endocrinology , blood pressure , renin–angiotensin system , alternative medicine , pathology
The safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of the angiotensin II (AII) AT 1 blocker irbesartan were assessed in healthy subjects. In this single‐center, placebo‐controlled, double‐blind within dose group, sequential, dose‐ascending study, 48 men were randomized to receive irbesartan at doses of 150 mg, 300 mg, 600 mg, or 900 mg daily. Subjects received a single dose of irbesartan (n = 9 per group) or placebo (n = 3 per group), followed by 3 days of placebo, and then multiple doses of irbesartan or placebo once daily for 7 days. The values for plasma area under the concentration—time curve (AUC) of irbesartan were dose proportional up to 600 mg. There were no significant differences between the dose groups in time to maximum concentration (t max ) or half‐life (t 1/2 ) after single and multiple doses. After multiple doses, urinary recovery was significantly lower in the 600‐mg and 900‐mg dose groups compared with the 150‐mg and 300‐mg dose groups. Steady‐state concentrations of irbesartan were achieved within 3 days of administration with no clinically important accumulation. Irbesartan produced dose‐dependent increases in plasma renin activity and AII levels. Irbesartan was well tolerated at doses from 150 mg to 900 mg daily; a maximally tolerated dose was not reached. Modest decreases in blood pressure without orthostatic symptoms were observed at irbesartan doses of 300 mg or higher. These results demonstrated the dose‐proportionality of irbesartan 150 mg to 600 mg and indicated that doses up to 900 mg daily were well tolerated.