Bernard E. Ilson

Pharmacokinetics and Protein Binding of Eprosartan in Healthy Volunteers and in Patients with Varying Degrees of Renal Impairment

This was an open‐label, parallel group study to compare the pharmacokinetics of multiple oral doses of eprosartan in subjects with normal renal function (Clcr >80 mL/min; n = 8) and patients with mild (Clcr 60–80 mL/min; n = 8), moderate (Clcr 30–59 mL/min; n = 15), or severe (Clcr <30 mL/min; n = 3) renal insufficiency. Each subject received oral eprosartan 200 mg twice daily for 6 days and a single dose on day 7. Mean total maximum concentration (Cmax) and area under the concentration—time curve from 0 to 12 hours (AUC0–12) were similar for healthy subjects and those with mild renal impairment, but were an average of 25% to 35% and 51% to 55% greater for patients with moderate and severe renal impairment, respectively, compared with healthy subjects. Mean renal clearance (Clr), which was similar for healthy subjects and patients with mild renal impairment, was decreased an average of 41% and 95% in the groups with moderate and severe renal impairment, respectively, compared with normal subjects. Eprosartan was highly bound to plasma proteins in all groups; however, the unbound fraction was increased approximately two‐fold in the group with severe renal impairment. Mean unbound Cmax and AUC0–12 were an average of 53% to 61% and 185% to 210% greater for the patients with moderate and severe renal impairment, respectively, compared with healthy subjects. Headache was the most common adverse experience reported in all subgroups. Eprosartan was safe and well tolerated regardless of degree of renal impairment. Cmax and AUC were increased and renal clearance decreased in patients with moderate to severe renal impairment in comparison to healthy subjects and patients with mild renal impairment. However, based on the moderate renal clearance and known safety profile of eprosartan, it is not necessary to adjust the dose of eprosartan in patients with renal insufficiency.

Pharmacokinetics of intravenously and orally administered eprosartan in healthy males: absolute bioavailability and effect of food

Eighteen healthy males received a single 300 mg oral dose of eprosartan as the commercial wet granulation formulation under fasting conditions and following a high‐fat breakfast and a single 20 mg intravenous (i.v.) dose. The pharmacokinetics of i.v. eprosartan (mean±S.D.) were characterized by a low systemic plasma clearance (131.8±36.2 mL min−1) and a small steady‐state volume of distribution (12.6±2.6 L). Oral bioavailability averaged 13.1%, due to incomplete absorption. In vitro dynamic flow cell dissolution data showed that pH‐dependent aqueous solubility of eprosartan is one factor which limits absorption. Eprosartan terminal half‐life was shorter after i.v. (approximately 2 h) versus oral (approximately 5–7 h) administration, which may be due to detection of an additional elimination phase or absorption rate‐limited elimination following oral administration. Oral administration of eprosartan following a high‐fat meal compared with fasting conditions resulted in a similar extent of absorption (based on AUC), but a decreased absorption rate. Cmax was approximately 25% lower, and a median delay of 1.25 h in time to Cmax was observed when eprosartan was administered with food. These minor changes in exposure are unlikely to be of clinical consequence; therefore, eprosartan may be administered without regard to meal times.

A dose proportionality study of eprosartan in healthy male volunteers.

The present study investigated the proportionality of exposure after single oral doses of 100, 200, 400, and 800 mg of eprosartan, a nonpeptide, nonbiphenyl angiotensin II receptor antagonist, in 23 healthy young men. Eprosartan was safe and well tolerated. Exposure to eprosartan increased with dose but in a less than proportional manner. For each two‐fold dose increase, area under the concentration—time curve (AUC) increased an average of 1.6 to 1.8 times and maximum plasma drug concentration (Cmax) increased an average of 1.5 to 1.8 times. For both parameters, the greatest difference from the dose multiple was observed between the 400‐ and 800‐mg doses. Dose proportionality of eprosartan, as assessed by an equivalence‐type approach using the 100‐mg dose as the reference and a 30% acceptance region (0.70, 1.43), was achieved for the 200‐ and 400‐mg doses for AUC and the 200‐mg dose for Cmax. The observed changes in the pharmacokinetics of eprosartan suggest slight saturation of absorption of eprosartan over the 100‐ to 800‐mg dose range, most likely due to the physicochemical properties of the drug (pH‐dependent aqueous solubility and lipophilicity).

The effects of eprosartan, an angiotensin II AT1 receptor antagonist, on uric acid excretion in patients with mild to moderate essential hypertension.

The effects of antihypertensive agents, including angiotensin II receptor antagonists, on urine uric acid excretion may have important clinical consequences. Therefore, the effects of single and repeated doses of eprosartan on uric acid excretion were evaluated in 57 male patients with mild‐to‐moderate essential hypertension in a double‐blind, randomized, placebo‐controlled, repeated dose, dose‐rising, two‐period, period‐balanced, crossover study conducted in two parts. In part 1 (n = 33), the effects of eprosartan dose regimens of of 50 mg, 100 mg, and 350 mg once daily and 150 mg every 12 hours on uric acid excretion were assessed. In part 2 (n = 24), the effects of eprosartan dose regimens of 600 mg, 800 mg, and 1,200 mg once daily on uric acid excretion were assessed. Eprosartan was well tolerated. There were no appreciable changes from predose values in fractional excretion of uric acid (FEua), urine uric acid excretion, urine uric acid to creatinine (Uua/Ucr) ratios, or serum uric acid concentrations after single or repeated doses of eprosartan. Mean Uua/Ucr ratios for eprosartan doses of 50 mg, 100 mg, or 350 mg daily or 150 mg every 12 hours were comparable to those for placebo. Mean FEua values and Uua/Ucr ratios for eprosartan doses of 600 mg, 800 mg, or 1,200 mg daily also were comparable to those for placebo. Single and repeated oral doses of eprosartan ranging from 50 mg to 1,200 mg daily had no effect on serum uric acid concentrations or urine uric acid excretion in patients with mild‐to‐moderate essential hypertension.

Pharmacokinetics and pharmacodynamics of SB 209670, an endothelin receptor antagonist: effects on the regulation of renal vascular tone.

To evaluate the pharmacokinetics and pharmacodynamics of an infusion of SB 209670, a nonpeptide endothelin‐A/endothelin‐B receptor antagonist.

Pharmacokinetics and Protein Binding of Eprosartan in Hemodialysis-Dependent Patients with End-Stage Renal Disease

Study Objectives. To compare eprosartan pharmacokinetics in hemodialysis patients and in volunteers with normal renal function, and to determine the effect of hemodialysis on these values.

Eprosartan, an Angiotensin II Receptor Antagonist, Does Not Affect the Pharmacodynamics of Glyburide in Patients with Type II Diabetes Mellitus

The potential for eprosartan, a nonbiphenyl tetrazole angiotensin II receptor antagonist, to affect the 24‐hour plasma glucose profiles in type II diabetic patients treated with glyburide was investigated in this randomized, placebo‐controlled, double‐blind (eprosartan—placebo phase only), two‐period, period‐balanced, crossover study. All patients received a stable oral dose (3.75–10 mg/day) of glyburide for at least 30 days before the first dose of double‐blind study medication was administered. Patients were randomized to receive either 200‐mg oral doses of eprosartan twice daily or matching oral placebo doses concomitantly with glyburide for 7 days during each treatment period. After a minimum washout period of 14 days, patients were crossed over to the alternate treatment. Serial samples to measure glucose concentrations in plasma were collected over a 24‐hour period on the day before administration of eprosartan or placebo and again on day 7. Mean glucose concentrations were comparable between treatment groups before administration of eprosartan or placebo. The point estimate (90% confidence interval) for the ratio of the average mean 24‐hour plasma glucose concentrations of eprosartan + glyburide to placebo + glyburide after 7 days of administration was 0.96 (0.90, 1.01). Eprosartan did not significantly alter the 24‐hour plasma glucose profile in patients with type II diabetes mellitus who were previously stabilized on glyburide.

Eprosartan does not affect the pharmacodynamics of warfarin

Eprosartan is an angiotensin II receptor antagonist being developed for the treatment of hypertension and heart failure. The effect of eprosartan on the steady‐state anticoagulant activity of warfarin was evaluated in 18 healthy male volunteers. Each subjects daily warfarin dose was titrated over 9 days to achieve a stable international normalized ratio (INR) of 1.3 to 1.6 by day 14. After the 14‐day warfarin titration phase, subjects were randomized to receive either eprosartan 300 mg or matching placebo twice a day for 7 days. All subjects continued to take the warfarin dose established during the 14‐day titration phase. The anticoagulant activity of warfarin was statistically equivalent when coadministered with eprosartan or with placebo. No serious or unexpected adverse events suggestive of abnormal bleeding occurred during coadministration of eprosartan and warfarin. As measured by the INR, there is no apparent effect of eprosartan on the anticoagulant effect of warfarin.

A dose‐response study to assess the renal hemodynamic, vascular, and hormonal effects of eprosartan, an angiotensin II AT1‐receptor antagonist, in sodium‐replete healthy men

The effects of orally administered eprosartan on changes induced by angiotensin II in blood pressure, renal hemodynamics, and aldosterone secretion were evaluated in healthy men in this double‐blind, randomized, single‐dose, placebo‐controlled crossover study, which was conducted in three parts. Part 1 (n = 12) assessed the onset and duration of the effect of eprosartan 350 mg or placebo; part 2 (n = 14) assessed the dose‐response profile of placebo or 10, 30, 50, 70, 100 or 200 mg eprosartan; and part 3 (n = 5) assessed the duration of the effect of 50, 100, or 350 mg eprosartan.