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.

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

“…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).…”

“…6,14,15 Steady-state plasma levels are reached in 3 days after daily dosing, and no clinically important accumulation (Ͻ20%) occurs (Table 6b). 6,14,15,110,129 The Vd of irbesartan is between 53 L and 93 L, and it has a Cl T of 157-177 mL/min (Table 6b). 14,15,126 Irbesartan has a long plasma elimination t .…”

“…(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.…”

“…145,148 Valsartan is not metabolised by the cytochrome P450 enzymes, 14,15 but is converted to inactive compounds (15-20% of the dose), 14,15,145 with only 9% in the circulation. 146,148 Pharmacokinetics of angiotensin receptor blockers in special populations (Table 8) No gender differences are observed in the pharmacokinetic parameters of candesartan, 12,14,15 eprosartan, 11,149 EXP3174, 14,15 irbesartan, 6,14,15,32,41,150 and valsartan. 14,15 But, female subjects were found to have twice as high C max for losartan 14,15 and telmisartan 15 as in males; the AUC of telmisartan is also higher (250%) in females than in males.…”

Angiotensin II receptor pharmacology and AT1-receptor blockers

“…The IC 50 was measured in various isolated tissues, for example, aorta, ileum, and in cultured cells, and values ranged from 0.8 to 4.1 nmol/L. 26,102 The IC 50 for the AT 2 receptor is reported to be 10 mol/L, the selectivity factor for the AT 1 receptor over the AT 2 receptor is, therefore, in the range of 10 000-fold. 102 In the rabbit aorta, irbesartan (1-10 nmol/L) leads to a dose-dependent blockade of Ang II-induced contractions.…”