Pharmacokinetics and Pharmacodynamics of Irbesartan in Patients with Hepatic Cirrhosis

Abstract

The effect of hepatic impairment on the clinical pharmacology of the angiotensin II (AII) receptor antagonist irbesartan was assessed by comparing pharmacokinetic and pharmacodynamic parameters in 10 patients with hepatic cirrhosis with a matched group of 10 healthy volunteers. The pharmacokinetics and pharmacodynamics of irbesartan, 300 mg taken orally once daily, were evaluated after single- and multiple-dose (7 consecutive days) administration to normotensive subjects in an open-label, multiple-dose, parallel group study. Pharmacokinetic data obtained after administration of single and multiple doses of irbesartan showed no significant difference between the two groups in time to maximum observed plasma concentration of drug (tmax), half-life (t1/2), area under the plasma concentration-time curve (AUC), apparent oral clearance (Cl(t)/F), renal clearance (Cl(r)), and accumulation index (AI). Steady-state levels of irbesartan were reached within 3 days in both treatment groups. After irbesartan administration on day 1, mean increases from baseline in plasma AII levels and plasma renin activity (PRA) were greater in the group with cirrhosis than in the control group. On day 7, mean increases from baseline in PRA were greater in the control group than in the group with cirrhosis. No discontinuations or serious adverse events occurred during the study. The pharmacokinetics of irbesartan after repeated oral administration were not significantly affected in patients with mild-to-moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency.

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…Irbesartan is not removed by hemodialysis (Sica et al, 1997). The pharmacokinetics of irbesartan were not significantly altered upon repeated oral administration in patients with mild to moderate cirrhosis of the liver (Marino et al, 1998b), and no dosage adjustment is required in such patients. Severe hepatic impairment has not been tested.…”

Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension

“…14,15,152,153 However, dose adjustment may be necessary in volumeor salt-depleted patients. 153 No significant differences were found in the pharmacokinetic parameters of irbesartan in patients with hepatic insufficiency and healthy subjects, 61,152 hence, no dosage adjustment is necessary in these patients. 14,15,61,152 Aging does not influence the pharmacokinetics of losartan.…”

“…153 No significant differences were found in the pharmacokinetic parameters of irbesartan in patients with hepatic insufficiency and healthy subjects, 61,152 hence, no dosage adjustment is necessary in these patients. 14,15,61,152 Aging does not influence the pharmacokinetics of losartan. 14,15 Rare cases of poor metabolisers of losartan (who convert only 1% of the dose of losartan to EXP3174) have been have been reported.…”

“…6,14,15,32,126,127 Peak plasma levels of irbesartan are achieved at 1.3-3 h after oral dosing. 6,32,41,61,110,[126][127][128][129] Irbesartan displays linear doserelated pharmacokinetics over the dose range of 50-600 mg. 6,14,15,110 The drug is 90% bound, mainly to albumin (binding to alpha 1-acid glycoprotein = 22%). 6,14,15 Steady-state plasma levels are reached in 3 days after daily dosing, and no clinically important accumulation (Ͻ20%) occurs (Table 6b).…”

“…(11-18 h). 6,14,15,32,41,61,110,[126][127][128] The hepatic extraction ratio of irbesartan is low (0.2), 126 and the drug is partially metabolised (6% of the dose) by oxidation (by cytochrome CYP2C9) and glucuronidation to form eight inactive metabolites. 14,15,130 The metabolites account for only 9% of the circulating drug, 5-10% in urine and 6% in faeces.…”