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PHARMACOKINETICS |
From the Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, Alabama (Dr Ravis); Pharmacia Laboratories, Stokie, Illinois (Ms Reid, Dr Roniker, Dr Tolbert); and Division of Nephrology, Medical College of Virginia of Virginia Commonwealth University, Richmond (Dr Sica).
Address for reprints: William R. Ravis, Pharmacal Sciences, 407 Walker Building, Auburn University, AL 36849.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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.093). The inactive metabolite and inactive ring-opened form displayed greater AUCs in renal impairment. Hemodialysis removed approximately 10% of the eplerenone dose. Eplerenone 100 mg once daily was well tolerated in all groups. Considering that renal function had no significant effects on eplerenone CL/F and that eplerenone metabolites are inactive, no dose adjustment appears necessary in patients with renal dysfunction.
Key Words: Eplerenone • renal disease • pharmacokinetics • hemodialysis • renal impairment
Aldosterone has been linked to high blood pressure, renal injury, cardiac hypertrophy, cardiac and vascular fibrosis, and ventricular arrhythmias as well as the increased mortality characteristic of the heart failure process.2-7 Because of these protean manifestations, aldosterone has become an attractive target for therapeutic intervention. Early belief held that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), by altering production and effect of angiotensin II, would eliminate an important stimulus to aldosterone production and thereby decrease systemic levels. However, although levels of aldosterone fall when these compounds are administered, the phenomenon is short lived. Soon after therapy is begun with either an ACE inhibitor or an ARB, aldosterone escape occurs, with aldosterone levels returning to baseline levels or higher.8,9 In this regard, aldosterone blockade with eplerenone may be a useful adjunctive therapy to ACE inhibitors or ARBs in patients with or without hypertension or end-organ disease, otherwise not adequately controlled on ACE inhibitors or an ARB.5,10,11 Clinical indications for eplerenone currently include the treatment of hypertension and eventually should include the treatment of heart failure in the post-myocardial infarction patient.5,12
Eplerenone pharmacokinetics has been studied over a range of 10- to 1000-mg oral doses.2 These studies show that eplerenone is well absorbed orally, with a half-life ranging from 2.2 to 9.4 hours.2 Eplerenone is chemically and enzymatically interconvertible with SC-70303, a ring-opened form of lactone. SC-70303 is inactive and, due to interconversion, exists in equilibrium with eplerenone. The major metabolite is SC-71597, a 6ß-OH metabolite of eplerenone, and this too is inactive. Based on studies with 14C-drug, approximately 5% of the oral dose is excreted as eplerenone and SC-70303 and 67% of the dose as drug and 14C-metabolites.2 The minimally effective dose of eplerenone was found to be 25 mg in a single-dose trial in healthy volunteers.2 The results of a comparative study versus spironolactone suggested that the pharmacodynamically effective dose for eplerenone is 100 mg.2
The objective of these studies was to evaluate the effect of varying degrees of renal function on the oral pharmacokinetics of eplerenone as observed after single and multiple dosing. Subjects were categorized into normal, mild, moderate, severe, and hemodialysis groups, and possible pharmacokinetic changes were identified by comparison with gender-, weight-, and age-matched normal subjects. In addition, the dialysis clearance and fraction of the dose removed by hemodialysis were determined.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Subject Population
A sufficient number of subjects were enrolled to ensure that a total of 32 evaluable subjects were entered into each of the 2 groups (normal and renally impaired). Subjects were stratified based on creatinine clearances (CLcr) as follows: normal renal function (CLcr >80 mL/min), mild renal impairment (CLcr = 50-80 mL/min), moderate renal impairment (CLcr = 30-49 mL/min), severe renal impairment (CLcr < 30 mL/min), and hemodialysis. Normal, healthy subjects were matched to renally impaired subjects with respect to gender, age (±10 years), and weight (±30%).
Subjects' eligibility included age 18 to 79, weight 50 kg and an ideal body weight no more than 30% greater than normal, blood pressure reading 
180/100 mm Hg or within clinical boundaries of acceptability, and negative results for hepatitis B surface antigen test and drug toxicology (including ethanol). Exclusion criteria included a history of any clinically significant illness other than chronic renal insufficiency; known hypersensitivity to eplerenone, spironolactone, or other steroid-based aldosterone-receptor antagonist compounds; use of diuretics, ACE inhibitors, clonidine, and/or 
blocking agents (unless authorized by the sponsor and maintained at a stable dose); aspartate aminotransferase or alanine aminotransferase 1.5 times the upper normal limits or any other laboratory abnormalities other than those related to chronic renal insufficiency or diabetes; significant substance abuse, drug addiction, or alcoholism within 3 years prior to enrollment in the study; use of a tobacco product within 48 hours of the pretreatment period; history of renal transplant; anemia (hematocrit 30%, hemoglobin <9 g/dL in chronic renal insufficiency subjects); urinary incontinence; 12-lead electrocardiogram (ECG) indication of any clinically pertinent abnormality; any investigational medication within 30 days of these studies; and donation of blood products within 30 days prior. The following drug products were permitted: acetaminophen (<2000 mg/d as needed for pain relief), eythropoietin, calcium carbonate, ranitidine, famotidine, misoprostol (cimetidine was prohibited), multivitamins, magnesium supplements, and heparin.
A pretreatment screening visit was conducted 21 days prior to the subject's return to the clinic for baseline evaluation on day-1 (ie, on days -21 to -2). A complete medical history and physical examination were performed. Additional testing procedures included a 12-lead ECG, vital signs, a battery of clinical laboratory tests, alcohol and drug toxicology screening, hepatitis B surface antigen test, and serum pregnancy test (for women of childbearing potential). Negative screening results from the alcohol and drug toxicology screening, the hepatitis B surface antigen screen, and the pregnancy test (if applicable) were required before study drug administration on day 1.
For those prospective subjects not on hemodialysis, a 24-hour urine collection with an accompanying serum creatinine were collected to determine CLcr. CLcr values were used to establish subject eligibility and placement in subject groups. CLcr was measured twice during the screening period. If the 2 values differed by more than 30%, a third CLcr was obtained. The average of the 2 (or 3, if needed) CLcr values was to be used for stratification into 1 of the renal function groups.
On day 9, a posttreatment physical examination (including vital signs, weight, and 12-lead ECG) and clinical laboratory tests were performed on each subject.
Study Design
This was a stratified, open-label, parallel-group study in which single and multiple eplerenone doses (100 mg) were administered to 2 groups of subjects: 32 healthy subjects and 32 subjects with varying degrees of renal impairment. Subjects received eplerenone 100 mg once daily on day 1 (single dose) and days 3, 4, 5, 6, 7, and 8 (multiple-dosing phase). The drug was given under fasting conditions (-12 to 4 hours) on day 1 and day 8 and with food on days 4 to 7. Serial blood and urine samples were obtained on day 1 (for up to 48 hours postdose) and day 8 (for up to 24 hours postdose) to assess the effect of renal impairment on the pharmacokinetic profile of eplerenone. Twenty-four-hour CLcr values were determined on days -1 to 3 (24 hours predose through 48 hours postdose) and days 8 to 9 (0-24 hours postdose). Safety was assessed based on a combination of physical examination, clinical laboratory tests, and monitoring of adverse events.
Each normal subject was to correspond to a previously recruited renally impaired subject by gender, age (±10 years), and weight (±30%). Group A were normal matches, and groups B, C, D, and E were renally impaired subjects.
Group A (normal healthy): 32 subjects with 24-hour CLcr values >80 mL/min.
Group B (mild): 8 subjects with 24-hour CLcr values of 50 to 80 mL/min.
Group C (moderate): 8 subjects with 24-hour CLcr values of 30 to 49 mL/min.
Group D (severe): 8 subjects with 24-hour CLcr values of <30 mL/min but not on dialysis.
Group E (hemodialysis): 8 subjects on hemodialysis with no or negligible urine output.
The entire study duration was 9 days. Subjects received 100-mg oral doses of eplerenone at approximately 8:00 AM under fasting conditions on days 1 and 8 and in a nonfasting state on days 4 to 7, administered by the clinical facility staff. Dosing times for dialysis subjects were adjusted based on dialysis schedule considerations.
Plasma samples for determination of eplerenone and metabolite concentrations were obtained on days 1 to 3 (15 minutes predose continuing for 48 hours postdose), days 5 to 7 (15 minutes predose only), and days 8 to 9 (15 minutes predose continuing through 24 hours postdose). Dialysis subjects provided arterial and venous blood samples as well on days 1 and 8 during hemodialysis. Urine samples for CLcr determination and pharmacokinetic analysis (groups A-D only) were to be collected on days -1 to 3 (24 hours predose through 48 hours postdose) and days 8 and 9 (0 to 24 hours postdose). On day 6, a predose blood sample was collected for electrolyte determination. In hemodialysis subjects (group E), dialysis was started 2 hours after the dose on day 1 and day 8, and paired arterial and venous blood samples and total volume dialysate were obtained hourly during the dialysis session.
Assay Procedure
Blood and urine samples were analyzed for eplerenone, SC-71597, and SC-70303 concentrations, and dialysate samples were analyzed for eplerenone and SC-70303 concentrations at Searle Laboratories (Skokie, Ill). A validated liquid chromatography/tandem mass spectrometry assay was used for the quantitation of SC-66110, SC-70303, and SC-71597 in human plasma and urine.13,14 Using stable isotopes of drug and metabolites as internal standards, plasma and urine supernatants were extracted on a C18 solid-phase extraction cartridge. Chromatographic separation was performed on a Zorbax XDB-C8 high-performance liquid chromatography column using a mobile phase of acetonitrile/water (40/60) with 10 mM ammonium acetate. Analytes were ionized using negative-to-positive switch electrospray mass spectrometry with multiple reaction monitoring with a tandem spectrometer for detection. For drug and metabolite, the precursor to product transitions were m/z 415 
163 and m/z 431 337, respectively.
Prestudy control assays were conducted to determine the accuracy, specificity, sensitivity, and reproducibility of the assays. For this study, the interday and intraday coefficients of variation for eplerenone and metabolites ranged from 1.2% to 10.2% and 0.7% to 9.7%, respectively. The limit of quantification for eplerenone and the 2 metabolites was 10 ng/mL in plasma and 50 ng/mL in urine.
Pharmacokinetic and Data Analysis
Pharmacokinetic parameters for drug and metabolites were determined by noncompartmental methods. Calculated parameters included half-life (t1/2), elimination rate constant (Ke), area under the plasma concentration-time curve to the last detectable plasma concentration (AUC0-t), area under the plasma concentration-time curve extrapolated to infinity (AUC), apparent clearance (CL/F), apparent clearance divided by weight (CL/F/WT), the maximum observed plasma concentration (Cmax), time of peak concentration (Tmax), and apparent volume of distribution (Varea/F). AUCs were determined by application of the trapezoidal rule. The elimination rate constant was estimated as the slope from linear regression of the natural log of concentration versus time from data points in the terminal phase of drug elimination. AUC values for single doses were determined as the AUC0-t plus the last concentration divided by Ke. On the last dose (day 8), parameters of Cmax, Tmax, area under the curve for the dosing interval (AUC0-24), CL/F, and CL/F/WT were estimated. Following a single dose, renal clearance (CLrenal) was calculated as the amount unchanged in the urine up to 48 hours divided by AUC. CLrenal during multiple dosing was determined as the amount excreted unchanged in 24 hours divided by AUC0-24. The nonrenal clearance (CLnonrenal/F) was estimated as CL/F minus CLrenal.
The hemodialysis clearance (CLhem) was calculated as
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where Cdialysate(i) and Vdialysate(i) are the drug or metabolite concentration in the dialysate and the volume of dialysate during period i. Cstart and Cfinish are the arterial plasma concentrations of drug or metabolite at the beginning and end of the dialysis period.
The effect of renal impairment on eplerenone, SC-71597, and SC-70303 pharmacokinetic parameters was tested with an analysis of variance (ANOVA) model, with subject group as the factor, for each matched pair separately. Prior to such analysis, values for AUC, Cmax, CL/F, CL/F/WT (for eplerenone only), and drug or metabolite in the urine (XU) were natural log-transformed. A 90% confidence interval (CI) was constructed for the ratio of the geometric least squares mean (LSM) of AUCs for each matched pair (renal impairment vs matched-normal subjects). The same CIs were produced for Cmax and XU and for eplerenone CL/F and CL/F/WT. The confidence intervals were constructed based on the log-transformed parameters. Tmax and t1/2 were compared based on the P value for the renal group comparison.
The linear relationship between renal function and eplerenone AUC, Cmax, and CL/F was examined using a linear regression model (log [pharmacokinetic parameter] = + ß CLcr) for both single-dose and multiple-dose administration. A similar analysis was performed on SC-71597 and SC-70303 AUC and Cmax parameters. The linear pharmacokinetics of eplerenone, SC-71597, and SC-70303 were investigated within each of the matched pair groups via 95% CIs for the ratio of AUC(0-24) (multiple-dose) to AUC (single-dose) geometric LSM.
The influence of eplerenone administration on CLcr in renally impaired subjects was examined using a repeated-measures analysis using data from baseline, day 1 (0-24 and 24-48 hours), and day 8.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Eplerenone Plasma Concentration Profiles Following Single and Multiple Dosing
Mean eplerenone plasma concentrations for the stratified groups are shown following a single dose in Figure 1 and following 5 days of daily dosing on day 8 in Figure 2. In each figure, standard deviation bars for eplerenone plasma concentrations are displayed for the normal subjects. Comparison of eplerenone plasma concentrations by sample time between the groups demonstrated similar plasma concentrations for the mild, moderate, and severe subjects relative to their matched normal group. In both single-dose and multiple-dose phases, eplerenone plasma concentrations were similar to their matched normal subjects for these 3 groups. During the single- and multiple-dose periods, mean eplerenone plasma concentrations for hemodialysis subjects were greater than those for matched normal subjects from 0 to 2 hours postdose but then lower between 2 and 16 hours postdose, which may have related to the initiation of a hemodialysis session 2 hours after dosing.
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Half-life values were not significantly different between renal function groups and their matched normals, and mean t1/2 ranged from 3.16 to 6.81 hours. Although Cmax was not significantly affected by renal function, the time of peak concentration, Tmax, was significantly shorter in hemodialysis patients. Tmax in hemodialysis subjects was 1.28 ± 0.47 hours and that in the normal matches was 2.22 ± 0.75 hours.
In normal subjects, the percentage of eplerenone excreted unchanged ranged from 1.7% to 2.2%. Subjects with severe renal dysfunction displayed significantly lower excretion percentage of unchanged eplerenone (0.9% ± 0.3%). With decreasing renal function, CLrenal decreased. CLrenal was significantly less in the moderate and severe renal subjects when compared to their matches. CLnonrenal/F was not significantly influenced by the degree of renal function.
Eplerenone Pharmacokinetics Following Multiple Dosing
Eplerenone pharmacokinetic parameters determined at the completion of multiple dosing on day 8 also showed the same trends and led to similar conclusions as those from the single-dose phase of the study. Half-lives were not estimated from multiple dose results. The percentage differences in AUC0-24 between each group and their normal matches were -5.0%, 9.2%, 31.5%, and -19.3% for the mild, moderate, severe, and hemodialysis stratified groups, respectively. As in the case of single-dose results, the ANOVA and interval testing showed no significant difference in AUC0-24 and CL/F/WT between each group and their normal matches. Thus, based on single and multiple-dose phases studying the effects of a wide range of renal function on eplerenone pharmacokinetics, it can be concluded that renal function has no significant influence on eplerenone total body clearance. In normal renal function subjects, the percentage of the dose excreted unchanged as eplerenone was less that 3%. Because of the minor importance of renal clearance in the total elimination of eplerenone and the variability in AUC and CL/F among groups and normals, it is not unexpected that renal function appears to have limited effects on eplerenone clearance and AUC.
As in the case of single-dose profiles, hemodialysis subjects appeared to have a significantly shorter Tmax compared to normals. Counter to the trend of increasing AUC and decreasing CL/F values noted in moderate and severe renal dysfunction subjects, hemodialysis subjects showed a trend toward lower AUC and greater CL/F as compared to normal matches. However, AUC and CL/F differences were not significant as compared to these matched normals.
The percentage excreted unchanged as eplerenone was 2.0% to 2.9% in normal groups and is similar to that noted after a single dose. Severe renal dysfunction subjects showed lower percentage excreted of unchanged eplerenone. This is a result of lower CLrenal in moderate and severe renally impaired subjects. Again, CLnonrenal/F was not affected by decreasing renal function.
Linearity in pharmacokinetics was compared by determining the ratio of AUC for a single dose to AUC0-24 from the multiple-dose phases by subject. To evaluate this ratio, 95% CIs were calculated. For eplerenone in all normals, the ratio was 1.06 and the interval was 1.02-1.11. For renal dysfunction groups, the 95% CIs for the ratio of eplerenone AUCs were 0.85-1.11, 0.89-1.26, 0.86-1.07, and 0.83-1.07, for the mild, moderate, severe, and hemodialysis groups, respectively. Although the ratio in normals indicated a slight 6% increase in AUC during multiple dosing, across all groups, the ratio of multiple- to single-dose AUCs appears linear.
Correlation of Clearance Versus Renal Function
Plots of eplerenone CL/F and CLrenal versus normalized measured CLcr during single- and multiple-dose studies are shown in Figures 3 and 4. Regression equations for CL/F and CLrenal obtained during both single- and multiple-dose phases were
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Effect of Renal Function on Metabolite Plasma Concentrations
The effect of renal impairment on SC-71597 and SC-70303 pharmacokinetic parameters was examined using an ANOVA model, with subject group as the factor for each separate matched pair. Comparisons between impaired/matched-normal subject groups of the logarithmic LSM of the pharmacokinetic parameters were performed. Table IV presents, by renal group, AUC and percentage of the dose excreted for SC-71597 and SC-70303 during single- and multiple-dose phases. All normal matches are shown as 1 group.
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For SC-71597, AUCs were significantly greater in moderate, severe, and hemodialysis subjects as compared to matched normal subjects. For single-dose results, SC-71597 AUC was greater by 57.1%, 79.0%, and 32.3% for these 3 groups, respectively. AUCs of SC-71597 were 53.0% and 70.9% greater than normal matches for moderate and severe subjects during multiple dosing. Although these increases were significant, the 35.3% increase in this metabolite's AUC during multiple dosing in hemodialysis subjects was not significant.
For SC-70303, similar trends were noted with increases in AUC with decreasing renal function during both single- and multiple-dose phases. Percentage increases in metabolite AUC with decreased renal function appeared greater for the SC-70303 metabolite compared to SC-71597. SC-70303 AUC was 89.5%, 140%, and 142.3% greater than normals in moderate, severe, and hemodialysis subjects, respectively, following single doses of eplerenone. These AUC increases were significant. During multiple dosing with eplerenone, SC-70303 AUCs were 59.6%, 166.8%, and 91.6% greater than normal matches for the 3 groups. AUC increases were significant in both the severe renal failure and hemodialysis groups.
Hemodialysis of Eplerenone and Metabolite
Total volume dialysate was collected for 4 to 5 hours during 2 separate hemodialysis sessions, which were begun 2 hours after dosing on day 1 (single-dose study) and day 8 (multiple-dose study). During the dialysis session, 9737 ± 2343 µg of eplerenone was recovered in the dialysate during single-dose studies and 9626 ± 1929 µg of eplerenone during the multiple-dose phase. This corresponds to 9.7 ± 2.3% and 9.6 ± 0.9% of the administered dose for single- and multiple-dose conditions, respectively. Amounts of SC-70303 in the dialysate showed that 1084 ± 347 µg of this metabolite was removed after a single dose and 1110 ± 307 µg following multiple dosing on day 8. Concentrations of SC-71597 were low and inconsistent in the dialysate, and thus results were not calculated or reported. Based on arterial and venous eplerenone blood concentrations, the cross dialyzer CLhemo was estimated during both study phases. CLhemo for eplerenone was 539 ± 101 mL/min and 582 ± 115 mL/min for single- and multiple-dose periods, respectively.
Physiologic Effects
Although blood pressure fell in all study groups (data not reported), the variability in the change and the small number of subjects studied preclude any meaningful observation concerning the antihypertensive effect of eplerenone. Serum potassium values also modestly increased in all renal failure study groups (mild renal failure 
0.23 ± 0.22 mmol/L; moderate renal failure 0.35 ± 0.15 mmol/L; severe renal failure 0.16 ± 0.24 mmol/L; hemodialysis 0.11 ± 0.22 mmol/L) but in no instance required discontinuation of a study subject because of clinically relevant hyperkalemia. Serum potassium changes were not always predictable as to the magnitude change and typically were not progressive once an increase was demonstrated. For example, in 1 renal impairment subject with a CLcr of 47 mL/min, the day 9 serum potassium was 5.1 mmol/L whereas the baseline value was 5.5 mmol/L; in 1 severe renal impairment subject with a CLcr of 15 mL/min, the baseline serum potassium was 4.7 mmol/L and increased to 5.9 mmol/L by day 6 but dropped to 5.3 mmol/L at day 9.
Safety Evaluation and Adverse Effects
Thirty-seven subjects (19 matched-normal subjects and 18 renally impaired subjects) reported at least 1 adverse event during the study. The incidence of adverse events within the subject groups ranged from 43% to 75%. The only adverse events reported for more than 1 subject during a particular treatment were dizziness and headache. Headache had the highest incidence and ranged from 14% to 63% among matched-normal subjects and from 0% to 22% among subjects with renal impairment. All events were mild or moderate in severity, with the exception of a severe headache for a matched-normal subject in the moderate impairment group. No serious adverse events or adverse events causing withdrawal were reported.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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This parallel normal-matched group study was conducted to determine pharmacokinetics of eplerenone and its metabolites following both single and multiple doses in patients with varying stages of renal dysfunction including a cohort of patients with end-stage renal disease undergoing chronic maintenance hemodialysis. Eplerenone is extensively metabolized, and the metabolites are considered inactive. Preliminary studies have shown that approximately 5% of an eplerenone dose is excreted in the urine unchanged or as its ring-opened form, SC-70303.2 Chemical and enzymatic interconversion occurs between eplerenone and SC-70303, an open lactone ring form of eplerenone, which is considered inactive.2,15 The present study confirms the low renal excretion of eplerenone with less than 2% excreted unchanged in subjects with normal renal function during both single- and multiple-dose phases of the project. Because of the low dependence of eplerenone total body clearance on renal elimination, major pharmacokinetic changes and thereby recommendations for dose adjustments in subjects with renal dysfunction were not anticipated.
Although there was a trend of lower CL/F in subjects with moderate, severe, and dialysis-dependent end-stage renal failure, CL/F values adjusted for weight were not different between these groups and their normal-matched groups. Also, AUC and Cmax for eplerenone were not significantly influenced by renal function. The coefficients of variation for AUC values (34%) and weight-adjusted Cl/F (50%) were large within both patient and normal groups. Weight-adjusted AUC and Cl/F estimates for normal subjects were not different between groups. The fraction of eplerenone excreted unchanged significantly decreased with declining renal function to less than 1% of the dose in severe renal dysfunction subjects compared to approximately 2% in normal matches. Significant decreases in CLrenal were noted in moderate and severe subjects. Compared to normals, CLrenal decreased by 40% and 48% in subjects with moderate dysfunction during single- and multiple-dose studies, respectively, and decreased 65% and 59%, respectively, in severe dysfunction subjects. Since the fraction excreted unchanged for eplerenone is low, changes in eplerenone CLrenal did not influence overall eplerenone CL/F in any of the renal failure groups. Even in hemodialysis subjects in whom CL/F appeared greater than in normal matches, CL/F was not significantly different between these subjects and their normal matches during either single-dose or multiple-dose periods. Varea/F is a complex parameter affected by not only distribution but also clearance; however, no differences were noted in renal dysfunction groups from normal Varea/F values. No significant change in eplerenone t1/2 was noted with renal dysfunction, and this reflects the lack of influence of renal function on CL/F and Varea/F. Thus, no major alterations in eplerenone pharmacokinetics in renal failure patients could be demonstrated.
Regression of CL/F and CLrenal adjusted for weight as a function of CLcr showed significant correlations of both clearance parameters with degree of renal function. Since the portion of the dose excreted in the urine is very small, estimates of CLrenal were variable and not significantly different among normal subject groups. Based on graphic appearance and statistical significance, the correlation between CLrenal versus CLcr was stronger than that between CL/F and CLcr. This is expected based on the major contribution of metabolic clearance, and not CLrenal, toward CL/F. Correlations between CL/F or CLrenal and CLcr appeared to be similar whether these parameters were determined from single-dose or multiple-dose studies. CLcr was stable during the study with no significant change in this clearance between baseline assessments and intrastudy determinations. It would appear that eplerenone administration as conducted in this study did not alter renal function in normal or mild, moderate, and severe renal dysfunction subjects.
The plasma and urinary pharmacokinetics of the inactive metabolite and ring-opened form were also examined, and these parameters showed expected changes consistent with renal dysfunction. Previous oral studies with 14C-eplerenone in normal subjects found that approximately 5% of the dose is excreted as eplerenone and SC-70303 in the urine and 28% as SC-71597 (6ß-OH metabolite) in the urine.2 For normal subjects, the present study demonstrates similar results with less than 2% of the dose excreted as unchanged eplerenone, 8% as SC-70303, and 24% as SC-71597. As expected, the percentage of dose excreted as drug and metabolites declined as renal function decreased. For eplerenone, the percentage in the dose excreted in the urine was significantly less (1%) in the severe renal dysfunction group compared to normal matches (1.7%-2.4%). In both single- and multiple-dose periods, the percentage of SC-71957 excreted decreased from approximately 24% in normals to approximately 7% to 9% in severe dysfunction subjects. Across groups, as renal function decreased, the AUC for both SC-70303 and SC-71957 increased probably due to decreased renal clearance of these metabolites. For severe renal dysfunction subjects, the AUCs for SC-70303 and SC-71957 were 70% and 170% greater than for normal matches. Interestingly, hemodialysis subjects had AUCs for SC-70303 and SC-71957 that were approximately only 35% and 90% greater than for normals. Although this was a significant increase in metabolite AUC above normal matches, the percentage increases would be expected to be greater than that noted in severe subjects.
Although there were no significant differences in CL/F for any renal group compared to normal matches, the greatest mean CL/F was noted in the hemodialysis subjects during both single- and multiple-dose phases. As compared to matched normals, severe renal dysfunction subjects had a 25% decrease in eplerenone CL/F while hemodialysis subjects displayed a 10% to 24% increase in CL/F during single- and multiple-dose periods. Dialysis was performed 2 hours after the dose during both the single- and multiple-dose periods. Consistently, approximately 9.6% of the administered dose was removed during a 4-hour dialysis session. The removal of 10% of the dose during dialysis would not completely explain this increase in CL/F, particularly with no eplerenone CLrenal in these subjects. Eplerenone is approximately 50% bound to plasma protein,1-4 and thus, possible altered plasma protein binding of eplerenone in hemodialysis subjects would have minimal effects on clearance parameters. In addition, albumin levels were not different between hemodialysis subjects and normals.
Decreases in drug metabolism and metabolic clearance have been reported in end-stage renal patients15,16 but not increases in clearance. The fact that AUCs for SC-70303 and SC-71957 as well as eplerenone appeared lower in dialysis subjects than severe renal dysfunction subjects might suggest that the higher CL/F in dialysis subjects is probably not due to enhanced metabolism. A decrease in eplerenone oral bioavailability in hemodialysis subjects might explain the decrease trend in AUCs of both drug and metabolites. Hemodialysis subjects had a significantly shorter Tmax, suggesting possible differences in rate of eplerenone oral absorption in these subjects. Again, these increases in AUC and decreases in CL/F in hemodialysis subjects were not significant compared to matched normals and thus would not support the need for dose adjustment in end-stage renal patients.
In conclusion, eplerenone is a highly selective aldosterone receptor antagonist and is expected to have many of the beneficial clinical effects of its predecessor without side effects associated with nonselective aldosterone blockade. Eplerenone is extensively metabolized, with the metabolites being inactive. Since less than 5% of eplerenone is excreted unchanged in the urine, renal dysfunction has little effect on eplerenone pharmacokinetics, and thus no dose adjustment for patients with renal disease is required. However, empiric dose adjustment for eplerenone in renal failure remains a consideration based on the likelihood of developing clinically relevant hyperkalemia.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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