title: Pharmacokinetics and pharmacodynamics of irbesartan in healthy subjects.
abstract: The safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of the angiotensin II (AII) AT1 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 (tmax) or half-life (t1/2) 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.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Marino
authors.forename: K
authors.initials: K
authors.lastname: Langenbacher
authors.forename: N F
authors.initials: NF
authors.lastname: Ford
authors.forename: H D
authors.initials: HD
authors.lastname: Uderman
mesh_terms: D000293:Adolescent; D000328:Adult; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D000077405:Irbesartan; D008297:Male; D008875:Middle Aged; D013777:Tetrazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000077405:Irbesartan