Irbesartan does not affect the steady-state pharmacodynamics and pharmacokinetics of warfarin.
OBJECTIVE
To determine whether the initiation or titration of irbesartan alters the pharmacodynamics and/or pharmacokinetics of warfarin in a clinically significant manner, thereby requiring additional monitoring of the anticoagulant effect of warfarin.


METHODS
Daily doses of warfarin were administered to 16 healthy males for 21 days (10 mg on day 1 and 2.5-10 mg on days 2-21). Irbesartan (300 mg/day) or placebo was concomitantly administered on days 15-21. The pharmacodynamic parameters prothrombin time (PT) and prothrombin time ratio (PTR) were evaluated throughout the study. Plasma and urine samples were collected before and up to 24 h after administration on days 14, 15 and 21 for the determination of the maximum concentration (C(max)), time to reach C(max)(t(max)), the area under the concentration-time curve (AUC) of S-warfarin and the cumulative urinary excretion of warfarin and its metabolites. Pre-dose plasma samples were also collected to determine the C(min) of S-warfarin (days 12, 13, 14 and 21) and irbesartan (days 19, 20 and 21).


RESULTS
Analysis of PTR data revealed no significant difference between the group mean PTR values at day 22 and those at day 15 (P=0.699). S-warfarin concentrations in plasma and urine, as well as the urinary concentrations of the metabolites of warfarin, were not affected by concomitant single- or multiple-dose administration of irbesartan. Plasma C(min) concentrations of S-warfarin and irbesartan were also not affected.


CONCLUSIONS
No clinically important effect of irbesartan on the pharmacodynamics and pharmacokinetics of warfarin are likely to occur during concomitant administration; therefore, neither a dosage adjustment of irbesartan or warfarin nor any additional monitoring of the anticoagulant effect of warfarin is necessary.
Mangold
B
B
Bristol-Myers Squibb Pharmaceutical Research Institute, Waterloo Office Park, 161 Drive Richelle, Box 30, 1410 Waterloo, Belgium.
Gielsdorf
W
W
Marino
M R
MR
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D057911:Angiotensin Receptor Antagonists; D000925:Anticoagulants / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000494:pharmacology*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D000077405:Irbesartan; D008297:Male; D008875:Middle Aged; D011517:Prothrombin Time; D013777:Tetrazoles / Q000009:adverse effects / Q000494:pharmacology*; D014859:Warfarin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000925:Anticoagulants; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D013777:Tetrazoles; D014859:Warfarin; D000077405:Irbesartan