A Dose Proportionality Study of Eprosartan in Healthy Male Volunteers

Chapelsky, Martha C.; Martin, David E.; Tenero, David M.; Ilson, Bernard E.; Boike, Steven C.; Etheredge, Rickey C.; Jorkasky, Diane K.

doi:10.1002/j.1552-4604.1998.tb04374.x

Cited by 26 publications

(12 citation statements)

References 4 publications

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“…11 The dose-C max and dose-AUC relationships for single doses in the range of 100-800 mg of eprosartan, are less than proportional due to saturation of absorption. 122 Eprosartan is highly bound to plasma proteins (98%), 11,120,123 and has a small steady-state Vd (13 L). 11,118 It has a low systemic Cl T (Table 6b; 130 mL/min).…”

Section: Adverse Effects Of Angiotensin Receptor Blockersmentioning

confidence: 99%

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

2000

J Hum Hypertens

289

215

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Angiotensin II receptor blockers (ARBs) represent a new class of effective and well tolerated orally active antihypertensive agents. Recent clinical trials have shown the added benefits of ARBs in hypertensive patients (reduction in left ventricular hypertrophy, improvement in diastolic function, decrease in ventricular arrhythmias, reduction in microalbuminuria, and improvement in renal function), and cardioprotective effect in patients with heart failure. Several large long-term studies are in progress to assess the beneficial effects of ARBs on cardiac hypertrophy, renal function, and cardiovascular and cerebrovascular morbidity and mortality in hypertensive patients with or without diabetes mellitus, and the value of these drugs in patients with heart disease and diabetic nephropathy.The ARBs specifically block the interaction of angiotensin II at the AT 1 receptor, thereby relaxing smooth muscle, increasing salt and water excretion, reducing plasma volume, and decreasing cellular hypertrophy. These agents exert their blood pressure-lowering effect mainly by reducing peripheral vascular resistance usually without a rise in heart rate. Most of the commercially available ARBs control blood pressure for 24 h after once daily dosing. Sustained efficacy of blood pressure control, without any evidence of tachyphylaxis, has been demonstrated after long-term administration (3 years) of some of the ARBs. The efficacy of ARBs is similar to that of thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors or calcium channel blockers in patients with similar degree of hypertension. Higher daily doses, dietary salt restriction, and concomitant diuretic or ACE inhibitor administration amplify the antihypertensive effect of ARBs. The ARBs have a low incidence of adverse effects (headache, upper respiratory infection, back pain, muscle cramps, fatigue and dizziness), even in the elderly patients. After the approval of losartan, five other ARBs (candesartan cilexetil, eprosartan, irbesartan, telmisartan, and valsartan) and three combinations with hydrochlorothiazide (irbesartan, losartan and valsartan) have been approved as antihypertensive agents, and some 28 compounds are in various stages of development.The ARBs are non-peptide compounds with varied structures; some (candesartan, losartan, irbesartan, and valsartan) have a common tetrazolo-biphenyl structure. Except for irbesartan, all active ARBs have a carboxylic acid group. Candesartan cilexetil is a prodrug, while losartan has a metabolite (EXP3174) which is more active than the parent drug. No other metabolites of ARBs contribute significantly to the antihypertensive effect.Keywords: angiotensin receptor blockers; candesartan; eprosartan; irbesartan; losartan; telmisartan; valsartan; pharmacokinetics After oral administration, the ARBs are rapidly absorbed (time for peak plasma levels ‫؍‬ 0.5-4 h) but they have a wide range of bioavailability (from a low of 13% for eprosartan to a high of 60-80% for irbesartan); food does not influence the bioavaila...

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Section: Adverse Effects Of Angiotensin Receptor Blockersmentioning

confidence: 99%

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

2000

J Hum Hypertens

289

215

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“…The dose-proportionality of eprosartan was assessed in a crossover study in which 23 healthy male volunteers received single oral doses of 100 (reference dose), 200, 400, and 800 mg after a standard breakfast. 5 Although mean AUC and C max values showed substantial increases among doses (Figure 3), the increases were less than dose proportional over the range of 100-800 mg. Dose-proportionality of eprosartan was demonstrated for dose-normalized AUC and C max between the 100 and 200 mg, but not for 400 and 800 mg.…”

Section: Absorption and Bioavailabilitymentioning

confidence: 95%

Pharmacokinetics of Eprosartan in Healthy Subjects, Patients with Hypertension, and Special Populations

Bottorff

Tenero

1999

Pharmacotherapy

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After oral administration of eprosartan to healthy volunteers, bioavailability is approximately 13%, with peak plasma concentrations occurring 1-2 hours after an oral dose in the fasted state. Food slows the rate of absorption and changes the overall extent by less than 25%, which is unlikely to be of clinical consequence. Plasma concentrations increase in a slightly less than dose-proportional manner from 100-800 mg. There is no evidence of significant accumulation of eprosartan with long-term therapy. The drug's terminal elimination half-life is typically 5-9 hours after oral administration. The agent is highly protein bound (approximately 98%), with low plasma clearance (approximately 130 ml/minute) and small volume of distribution (approximately 13 L). It is primarily unmetabolized by the liver, with less than 2% of an oral dose recovered in the urine as a glucuronide. Biliary (primary) and renal excretion contribute to its elimination. No dosage adjustment is required in patients with mild to moderate renal impairment. Although an increase in systemic exposure to eprosartan was observed in the elderly, in patients with hepatic impairment, and in those with severe renal disease, this finding is unlikely to be of clinical consequence, based on the drug's excellent safety and tolerability profile (doses up to 1200 mg) in phase III clinical trials in hypertensive patients. Eprosartan can be safely administered to these special populations without an initial dosage adjustment, with subsequent dosing individualized based on tolerability and response.

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“…Such is the case for the AII receptor antagonist eprosartan. [19][20][21][22] Eprosartan is a novel nonbiphenyl, nontetrazole, nonpeptide, orally active AII receptor antagonist approved for the treatment of hypertension in 26 countries worldwide.…”

Section: Aii Receptor Antagonistsmentioning

confidence: 99%

The Renal Profile of Eprosartan

Sica

Hollenberg

1999

Pharmacotherapy

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The angiotensin II (AII) receptor antagonist eprosartan is a highly selective, nonpeptide drug specific for the AT1 receptor subtype that completely inhibits pressor, aldosterone secretory, and renal vasoconstrictive effects produced by AII infusions in healthy humans. It increases effective renal plasma flow in both salt-replete and salt-restricted healthy men, and maintains glomerular filtration rates in patients with essential hypertension and those with renal insufficiency after either single or multiple doses. In healthy salt-restricted men, the drug suppresses and stimulates aldosterone and renin, respectively, in the initial few hours after administration. This feedback inhibition for renin release and suppression of aldosterone is reduced with normal sodium intake. Eprosartan is natriuretic in salt-restricted subjects and does not induce sodium retention even when it reduces blood pressure. These properties, in addition to antagonism of AII effect at the AT1 receptor, no doubt contribute to the agent's antihypertensive effect in patients with essential hypertension. Pharmacodynamic studies predict that doses of up to 400 mg are safe. Additional preliminary studies suggest that doses as high as 1200 mg are safe and well tolerated, while producing meaningful hemodynamic and neurohumoral effects in patients with essential hypertension.

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A Dose Proportionality Study of Eprosartan in Healthy Male Volunteers

Cited by 26 publications

References 4 publications

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

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

Pharmacokinetics of Eprosartan in Healthy Subjects, Patients with Hypertension, and Special Populations

The Renal Profile of Eprosartan

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