Steven C. Boike

Steady‐State Pharmacokinetics of Carvedilol and Its Enantiomers in Patients with Congestive Heart Failure

Carvedilol is a relatively new drug with β‐and α1‐receptor blocking activity and antioxidant effects recently approved for the treatment of congestive heart failure (CHF). An ascending, multiple‐dose study was completed in 20 male patients with stable New York Heart Association (NYHA) Class III or IV CHF. The pharmacokinetics of carvedilol, S(−)‐carvedilol, R(+)‐carvedilol, and the active metabolites of carvedilol was assessed at steady state after twice‐daily oral administration of carvedilol for 7 days at 6.25, 12.5, 25, and 50 mg doses. Carvedilol exhibited stereoselective pharmacokinetics in CHF patients with dose‐proportional increases in steady‐state plasma concentrations of carvedilol and its enantiomers. Mean AUC and Cmax values for carvedilol were up to twofold higher in patients with Class IV CHF as compared to those with Class III CHF. Steady‐state plasma concentrations of the active metabolites also increased in a dose‐proportional manner and were typically 10% or less of that observed for carvedilol. In general, carvedilol was adequately tolerated by adult male CHF patients at the dose levels (6.25–50 mg) evaluated in this study as adverse events were consistent with those frequently observed in patients with CHF.

Use of topical corticosteroid pretreatment to reduce the incidence and severity of skin reactions associated with testosterone transdermal therapy

Local skin reactions at the application site are the most common adverse events associated with the testosterone transdermal delivery (TTD) systems used to treat postpubertal hypogonadism in males. This open-label, controlled pilot study was conducted to determine whether topical pretreatment with triamcinolone acetonide 0.1% cream might be useful in reducing the incidence and/or severity of chronic skin irritation when used in healthy volunteers receiving TTD systems. Adult male volunteers wore three topical systems, which were applied to the upper back daily (Monday through Friday) for 6 weeks: (1) TTD with no pretreatment of application site; (2) TTD with pretreatment of application site using triamcinolone acetonide 0.1% cream; and (3) an inactive occlusive dressing (control). On Monday through Thursday, systems were removed 24 hours after application. Patches applied on Friday were worn continuously for 72 hours until their removal on Monday. Skin reactions were graded on a scale from 0 to 4 (0 = none, 4 = severe) and were assessed daily by research personnel, beginning at the time of system removal (assessment 1) and on the two subsequent clinic visits (assessments 2 and 3). All skin irritation scores of all subjects were totaled for each treatment regimen to obtain a cumulative score per treatment regimen. The cumulative scores were also analyzed by assessment time and study week (weeks 1-6). Eighty-two subjects were enrolled in the study, and 65 completed the 6-week treatment course. Mean age of subjects was 24 years (range, 18-69 years), and mean weight was 79.0 kg (range, 58.9-127.3 kg). All subjects were white males. At assessment 1, pretreatment with triamcinolone acetonide 0.1% cream (compared with no pretreatment) was associated more often with scores of 0 (no erythema), with comparable occurrences of mild skin irritation, and with fewer occurrences of moderate erythema. At all three assessments, more subjects had lower cumulative scores with pretreatment than without pretreatment. At every assessment and in each week of the study, total weekly cumulative skin irritation scores were also lower with pretreatment than without pretreatment. No adverse experiences other than skin irritation were reported. Results of this study suggest that in patients using TTD systems, the incidence and severity of skin irritation at application sites may be reduced through pretreatment with triamcinolone acetonide 0.1% cream.

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.

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.

Bioequivalence Assessment of a Single 5 mg/day Testosterone Transdermal System Versus Two 2.5 mg/day Systems in Hypogonadal Men

A novel, nonscrotal, transdermal delivery system for testosterone therapy has been marketed for treatment of hypogonadal men. The usual dose of this system is two 2.5 mg/day systems applied daily. A new system has been developed that administers a dose of 5 mg/day using a single patch rather than two patches. A randomized, steady‐state, four‐period, replicate‐design, open‐label, crossover study was conducted to assess the bioequivalence of the two testosterone transdermal delivery systems in postpubertal, hypogonadal men: two 2.5 mg/day patches as the reference regimen (R) and one 5 mg/day patch as the test regimen (T). 21 men were enrolled, and 20 completed the study. Each subject was randomly assigned to one of four sequences (R1‐R2‐T1‐T2, T1‐T2‐R1‐R2, R1‐T1‐T2‐R2, T1‐R1‐R2‐T2), such that each subject received each regimen during two study sessions. Two subjects were inadvertently treated according to the sequence T1‐R1‐T2‐R2. Patches were applied to the upper arm, thigh, and back in the evening on days 1, 2, and 3, respectively, of each study session. Serial blood samples were obtained for pharmacokinetic analysis of testosterone for 24 hours after patch application on day 3 of each study session. The two formulations would be considered bioequivalent if the 90% confidence intervals (CI) for the ratios of the adjusted geometric means for T:R for both area under the concentration—time curve from 0 to 24 hours (AUC0–24) and maximum concentration (Cmax) were completely contained in the interval (0.80, 1.25). Mean values for AUC0–24 and Cmax were similar for the two formulations. The T and R formulations were found to be bioequivalent based on both AUC0–24 (90% CI 0.96, 1.08) and Cmax (90% CI 0.92, 1.07). The median time to Cmax was also similar, indicating comparable rates of testosterone absorption for both formulations. Based on this analysis, the testosterone transdermal system 5 mg/day patch is bioequivalent to two of the 2.5 mg/day patches. Both systems were safe and well tolerated in hypogonadal men.

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.