Pharmacokinetic and pharmacodynamic profile of rosuvastatin in patients with end-stage renal disease on chronic haemodialysis.

BACKGROUND: Rosuvastatin has been shown to provide effective treatment of dyslipidaemia in patients with end-stage renal disease (ESRD) undergoing haemodialysis, but data from controlled trials are very limited on the pharmacokinetics and pharmacodynamics of rosuvastatin in this population. OBJECTIVE: The aim of the present study was to better define the pharmacokinetic and pharmacodynamic profiles of repeated doses of rosuvastatin at a starting dose of 10 mg/day in a group of patients with ESRD. STUDY DESIGN: This was a single-centre, open-label study of rosuvastatin 10 mg daily, given over a 16-day treatment period in patients with ESRD undergoing chronic haemodialysis. SETTING: The study was carried out at a single site in the USA. PATIENTS: Patients aged 18-65 years with ESRD who had been on dialysis for ≥ 3 months were eligible for inclusion. Of 12 patients enrolled, 11 were included in the pharmacokinetic and pharmacodynamic analysis and all were included in the safety evaluation. The mean age of patients was 43.9 years (range 24-60 years). Five patients were Caucasian, six were black and one was Hispanic. INTERVENTION: Patients received an oral dose of rosuvastatin 10 mg once daily in the morning for 16 consecutive days. MAIN OUTCOME MEASURE: The primary objective was to estimate the degree of rosuvastatin accumulation in plasma by measuring the area under the plasma concentration time curve (AUC) from time zero to 24 h following a single dose of rosuvastatin 10 mg on day 1, and the AUC at steady state on day 15. RESULTS: Following administration of single and multiple doses, plasma concentrations of rosuvastatin declined in an apparent bi-exponential manner and remained above the limit of assay detection throughout the entire sampling periods on both day 1 and day 15. Steady-state plasma concentrations of rosuvastatin were achieved by day 11. Little accumulation of rosuvastatin after repeated, once-daily dosing was observed; the geometric mean accumulation ratio for rosuvastatin was 1.37 (coefficient of variation = 36.4 %). Clearance of rosuvastatin and its metabolites via dialysis was minimal. Following rosuvastatin 10 mg daily for 16 days, total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B were reduced from baseline by 30.6 %, 38.9 % and 30.6 %, respectively. Rosuvastatin was well tolerated. CONCLUSION: The degree of rosuvastatin accumulation observed in patients receiving dialysis is similar to that in healthy individuals. The results of the current study suggest that rosuvastatin 10 mg may be administered to patients with ESRD on chronic haemodialysis without need for dose reduction.

Renal effects of conivaptan, furosemide, and the combination in patients with chronic heart failure.

BACKGROUND: Loop diuretics, though often effective for treating congestion, have significant limitations. Discovering ways to limit exposure to loop diuretics while achieving effective decongestion is an important goal of current clinical research in heart failure (HF). Vasopressin antagonists are effective in removing large amounts of water, but not salt, in HF. Few data exist about the detailed renal and hormonal effects of these agents compared with or in combination with loop diuretics. This study investigated the renal and neurohormonal effects of loop diuretics, the mixed vasopressin antagonist conivaptan, and the combination in patients with chronic stable HF. METHODS AND RESULTS: In 8 patients with chronic stable HF on standard medical treatment, heart rate, arterial pressure, systemic vascular resistance, and cardiac output (the latter 2 by using impedance cardiography), as well as glomerular filtration rate (iothalamate clearance), renal blood flow (para-aminohippurate clearance), urinary volumes and urinary sodium, plasma catecholamines, renin activity, arginine vasopressin, and B-type natriuretic peptide were assessed before and at hourly intervals for 4 hours after receiving furosemide, conivaptan, or the combination on 3 different study days at a minimum of 1-week intervals. There were no significant effects of conivaptan, furosemide, or the combination on any hemodynamic variable, neurohormonal level, renal blood flow, or glomerular filtration rate. Conivaptan and furosemide similarly increased urine volumes; the effect of the combination was significantly greater. Furosemide, but not conivaptan, increased urinary sodium excretion, and the combination was significantly greater than after furosemide alone. CONCLUSIONS: Without adversely affecting important hemodynamic variables, neurohormones, renal blood flow, or glomerular filtration rate, conivaptan significantly augmented both the diuretic and the natriuretic response to furosemide in patients with chronic HF. These results may have implications for the design of furosemide-sparing regimens in the treatment of acute HF.

Pharmacokinetics and safety of sunitinib malate in subjects with impaired renal function.

This phase I, open-label, single-dose study evaluates the effects of severe renal impairment and end-stage renal disease (ESRD) requiring hemodialysis on the pharmacokinetics, safety, and tolerability of sunitinib and its primary active metabolite, SU12662. Subjects with normal renal function (creatinine clearance > 80 mL/min), severe renal impairment (creatinine clearance < 30 mL/min), and ESRD requiring hemodialysis receive a single dose of sunitinib 50 mg. Serial blood samples are collected for quantification of plasma concentrations using a validated liquid chromatography with tandem mass spectrometry assay. Safety is monitored. Twenty-four subjects complete the study. Pharmacokinetics in subjects with severe renal impairment appear similar to those with normal renal function. Plasma exposure to sunitinib and SU12662 appears lower in subjects with ESRD compared with subjects with normal renal function or severe renal impairment. Single-dose sunitinib 50 mg is well tolerated regardless of renal function. The currently approved starting dose of sunitinib 50 mg on Schedule 4/2 is expected to be appropriate for patients with renal impairment; any subsequent dose modifications should be based on patients' ability to tolerate treatment.

Multiple-dose pharmacokinetics of peginterferon alfa-2b in patients with renal insufficiency.

AIM: To evaluate the safety, tolerability and multiple-dose pharmacokinetics of pegylated interferon (PEG-IFN) alfa-2b in patients with moderate or severe renal insufficiency and in those with normal renal function. METHODS: In an open-label study, subjects with normal renal function (creatinine clearance >80 ml min(-1) per 1.73 m2) and patients with moderate (30-50 ml min(-1) per 1.73 m2) or severe (10-29 ml(-1) min(-1) per 1.73 m2) renal impairment received weekly injections of PEG-IFN alfa-2b (1.0 microg kg(-1)) for 4 weeks. Safety assessments were made before each injection and blood samples were taken up to 168 h after the final dose. RESULTS: Renal insufficiency increased PEG-IFN alfa-2b exposure. Area under the curve for 0-tau (dosing interval of 168 h), AUC(tau), was increased 30% and 120% in patients with moderate or severe renal insufficiency, respectively. Mean maximum serum concentration was almost doubled in patients with severe insufficiency [1305.8 pg ml(-1); 95% confidence interval (CI) 825, 1786] compared with subjects with normal renal function (731.4 pg ml(-1); 95% CI 407, 1056), whereas the apparent volume of distribution was reduced (0.80 l kg(-1)vs. 1.28 l kg(-1), respectively). Elimination half-life was extended in patients with moderate and severe renal insufficiency (65.6 h and 64.9 h, respectively) compared with subjects with normal renal function (51.5 h). Significant differences were observed in the AUC and C(max) values of patients with severe renal dysfunction, compared with those who had normal renal function (P < 0.05; Kruskal-Wallis test). PEG-IFN alfa-2b was well tolerated and adverse events were similar in both treatment groups. CONCLUSIONS: Exposure to PEG-IFN alfa-2b is increased in patients with renal insufficiency, suggesting that doses of the drug should be reduced by 50% in patients with severe renal insufficiency and by 25% in those with moderate insufficiency.

Pharmacokinetics and safety of ebastine in healthy subjects and patients with renal impairment.

OBJECTIVE: To assess the differences in the pharmacokinetics and cardiac safety of ebastine and its active metabolite, carebastine, in patients with normal and impaired renal function. METHODS: Twenty-four patients with varying degrees of renal impairment (mild, moderate or severe: n = 8 per group) and 12 healthy subjects participated in an open-label, parallel-group, multicentre study. Ebastine 20mg was administered orally once daily for 5 days. Plasma concentrations of ebastine and carebastine were determined for 24 hours on day 1 and for 72 hours on day 5 by using a validated sensitive liquid chromatography-tandem mass spectrometry assay with a minimum quantifiable limit of 0.05 ng/mL for ebastine and 1.00 ng/mL for carebastine. Renal function was assessed by measuring 24-hour creatinine clearance (CL(CR)) at baseline. Cardiac and general safety parameters were also monitored. RESULTS: The pharmacokinetics of ebastine were not modified by renal impairment. No correlation between ebastine pharmacokinetics and renal function, as expressed by CL(CR) assessed 2 days prior to dosing, was observed. Comparison of the plasma exposure and the elimination half-life of ebastine and carebastine between groups showed no significant differences. Therefore, no apparent accumulation of ebastine and carebastine occurred, and steady-state concentrations of ebastine and carebastine were predictable from single-dose pharmacokinetics for both healthy subjects and patients with renal impairment, even though the variability between the groups was large. In addition, no differences were observed in the safety of ebastine between patients with renal impairment and healthy subjects when assessing adverse events, vital signs, laboratory parameters or ECGs. CONCLUSION: Ebastine was generally well tolerated in subjects with impaired renal function. No clinically important pharmacokinetic or safety differences were observed between patients with renal impairment and healthy subjects with normal renal function.

Pharmacokinetics of maribavir, a novel oral anticytomegalovirus agent, in subjects with varying degrees of renal impairment.

The effect of renal function on the pharmacokinetics of maribavir, a novel anticytomegalovirus agent, was evaluated in 12 adults with normal renal function (creatinine clearance [CrCl] >80 mL/min) and 19 adults with renal impairment classified as mild (n = 5), moderate (n = 5), or severe (n = 9), as measured by CrCl 50-80, 30-49, and <30 mL/min, respectively. After a single oral dose of maribavir 400 mg, the pharmacokinetics of maribavir, based on total and unbound plasma concentrations, showed no statistically significant difference between subjects with normal renal function and subjects with mild/moderate or severe renal impairment. Renal impairment was associated with an increase in area under the plasma concentration-time curve (AUC) values for an inactive metabolite of maribavir, VP 44469. Results were consistent with those of previous studies, which showed that very little maribavir was excreted unchanged in urine, whereas about 22% of an oral dose of maribavir is recovered in urine as VP 44469.

Pharmacokinetic profile of rizatriptan 10-mg tablet and 10-mg orally disintegrating tablet administered with or without water in healthy subjects: an open-label, randomized, single-dose, 3-period crossover study.

This open-label, 3-period crossover study compared the plasma concentration profiles of rizatriptan tablet, orally disintegrating tablet with water (ODTc), and ODT without water (ODTs) in 24 healthy volunteers aged 18 to 45 years. At each period, subjects received a single dose of either 10-mg rizatriptan tablet, 10-mg rizatriptan ODTs, or 10-mg rizatriptan ODTc. The authors hypothesized that ODTc has a greater geometric mean AUC(0-2h) than ODTs and that ODTc has a greater geometric mean AUC(0-1h) than tablet. A secondary end point was to compare the time of occurrence of the maximum rizatriptan plasma concentration (t(max)) of each dosing method. ODTc had a statistically significantly greater geometric mean AUC(0-2h) compared with ODTs (33.84 h x ng/mL vs 18.83 h x ng/mL; P < .001). ODTc had a slightly, but not statistically significantly, greater geometric mean AUC(0-1h) compared with rizatriptan tablet (17.07 h x ng/mL vs 13.32 h x ng/mL). The median t(max) was 0.67 hours for ODTc and tablet and 1.33 hours for ODTs. ODTc showed a slightly, but not significantly, faster rate of absorption compared with tablet. ODTs with water had a faster rate of absorption than ODTc. Future studies are needed to determine whether this pharmacokinetic difference produces differential efficacy in a clinical setting.

Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease, and volunteers with renal dysfunction.

Micafungin is an antifungal agent metabolized by arylsulfatase with secondary metabolism by catechol-O-methyltransferase. The objectives of this study were to estimate the pharmacokinetic parameters and plasma protein binding of micafungin in volunteers with moderate hepatic dysfunction (n = 8), volunteers with creatinine clearance < 30 mL/min (n = 9), and matched controls (n = 8 and n = 9, respectively). Single-dose micafungin pharmacokinetics were estimated using noncompartmental techniques. There was a statistically lower area under the observed micafungin concentration-time curve (AUC) from time 0 to infinity for subjects with moderate hepatic dysfunction as compared to control subjects (97.5 +/- 19 microg.h/mL vs 125.9 +/- 26.4 microg.h/mL, P = .03), although there was no difference in micafungin weight-adjusted clearance (10.9 +/- 1.7 mL/h/kg vs 9.8 +/- 1.8 mL/h/kg, P = .2). The difference in area under the concentration-time curve may be explained by the differences in body weight between subjects and controls. Renal dysfunction did not alter micafungin pharmacokinetics.

Pharmacokinetics, safety, and tolerability of intramuscular ziprasidone in healthy volunteers.

Little has been published regarding the pharmacokinetics of the intramuscular (IM) formulation of Ziprasidone. The authors report results from 2 early phase I studies in healthy volunteers: a trial of single 5-, 10-, or 20-mg IM doses of ziprasidone in 24 subjects and an open-label 3-way crossover trial of 5-mg intravenous (IV), 5-mg IM, and 20-mg oral ziprasidone in 12 subjects. Absorption of IM ziprasidone was rapid (Tmax < 1 hour). The IM pharmacokinetic profile was consistent between studies and linear, with dose-related increases in exposure observed. The mean IM elimination t(1/2) was short and approximately 2.5 hours. The mean bioavailability for the 5-mg IM ziprasidone dose was approximately 100%. Adverse events were generally mild to moderate, and no subjects were discontinued from the study. No significant effects on renal function or other laboratory values were noted. These results support the use of IM ziprasidone in treating acutely agitated patients with schizophrenia.

A prospective comparison of three argatroban treatment regimens during hemodialysis in end-stage renal disease.

BACKGROUND: We prospectively evaluated 3 treatment regimens of argatroban, a direct thrombin inhibitor, for providing adequate, safe anticoagulation in patients with end-stage renal disease (ESRD) during hemodialysis. METHODS: In this randomized, 3-way crossover study, ESRD patients underwent hemodialysis sessions of 3- or 4-hour duration using high-flux membranes and each of 3 argatroban treatment regimens (A: 250-microg/kg bolus, with an additional 250-microg/kg bolus allowed; B: 250-microg/kg bolus followed by 2-microg/kg/min infusion; C: steady-state, 2-microg/kg/min infusion initiated 4 hours before dialysis). Pharmacodynamic effects including activated clotting times (ACTs); hemodialysis efficacy including single-pool Kt/V, urea reduction ratio (URR), and circuit flow; and safety through a 3-day follow-up were monitored. Argatroban pharmacokinetic parameters including dialytic clearance were evaluated during regimen C. RESULTS: Thirteen patients completed 38 hemodialysis sessions (1 patient withdrew consent after 2 sessions). Mean +/- SD ACTs increased from 131 +/- 14 seconds at baseline to 153 +/- 24, 200 +/- 30, and 197 +/- 33 seconds, respectively, after 60 minutes of hemodialysis using regimens A, B, and C. Across regimens, mean Kt/Vs (1.5-1.6) and URRs (70%-73%) were comparable. No dialyzer was changed; 1 session was shortened 15 minutes because of circuit clot formation. Systemic argatroban clearance increased approximately 20% during hemodialysis, without clinically significantly affecting ACTs. Upon argatroban discontinuation, ACTs and plasma argatroban decreased concurrently (elimination half-life, 35 +/- 6 min). No thrombosis, bleeding, serious adverse events, or clinically significant changes in vital signs or routine laboratory measures occurred. CONCLUSION: Argatroban, administered by each treatment regimen, provides safe, adequate anticoagulation to enable successful hemodialysis in ESRD patients. Argatroban dialytic clearance by high-flux membranes is clinically insignificant.

The pharmacokinetics and hemodynamics of sildenafil citrate in male hemodialysis patients.

BACKGROUND: Erectile dysfunction (ED) is highly prevalent in men with renal disease. The clearance of sildenafil citrate, a highly effective oral treatment for ED, is decreased in men with severe renal insufficiency, but the pharmacokinetic and hemodynamic profiles during maintenance hemodialysis in men with end-stage renal disease have not been studied. METHODS: Fifteen men undergoing chronic outpatient maintenance hemodialysis received a single 50-mg oral dose of sildenafil on 2 occasions, once 2 hours before, and once 2 hours after hemodialysis, with randomized assignment to sequence. Blood and dialysate samples were collected, and hemodynamic measurements were made. RESULTS: Hemodialysis did not significantly clear either sildenafil or its primary metabolite, UK-103,320. Administration after hemodialysis was associated with a 17% higher peak plasma concentration and earlier time to peak, which were not clinically meaningful, whereas the overall extent of absorption and the elimination half-life were not affected. The average extent of drug bound to plasma protein was approximately 96% in hemodialysis patients. Intradialytic hypotension was not observed more frequently when sildenafil was administered before hemodialysis. Systolic blood pressure tended to decrease less during hemodialysis when subjects were treated with sildenafil before dialysis. CONCLUSION: The present study demonstrates that sildenafil is not cleared by hemodialysis, and the pharmacokinetic profile resembles more closely that observed in normal volunteers than that observed in patients with severe renal insufficiency. In addition, we found that sildenafil does not promote intradialytic hypotension.

Pharmacokinetics and safety of the ketolide telithromycin in patients with renal impairment.

The pharmacokinetics and safety of the ketolide telithromycin were evaluated in two separate studies after single and repeat oral dosing in patients with varying degrees of renal impairment and in subjects with normal renal function. The single-dose study was an open-label, nonrandomized, parallel-group design in which all 40 patients received a single oral dose of telithromycin 800 mg. The repeat-dose study was an open-label study with a randomized, balanced, incomplete three-block treatment crossover design. In this study, each of the 36 patients received two of three telithromycin regimens (400, 600, or 800 mg once daily for 5 days), with a washout period of >/= 7 days between treatments. Telithromycin was well tolerated. Adverse events were generally mild in severity, and no serious drug-related adverse events were reported. Plasma exposure to telithromycin (C(max), AUC) showed a tendency to increase with increasing severity of renal impairment in both studies. In patients with severe renal impairment (CL(CR) < 30 mL/min) receiving telithromycin 800 mg in the repeat-dose study, C(max,ss) and AUC((0-24 h)ss) increased 1.5-fold (p < 0.05) to 2.0-fold (p = 0.0005), respectively, compared with healthy subjects. The percentage of dose excreted in urine and renal clearance (CL(R)) of telithromycin was found to decrease significantly with increasing severity of renal impairment in both studies, and CL(R) was found to be independent of telithromycin dose in the repeat-dose study. In conclusion, telithromycin dosage adjustment is not necessary in patients with mild to moderate renal impairment (CL(CR) >/= 30 mL/min). In patients with severe renal impairment (CL(CR) < 30 mL/min), dosage adjustment could be considered.

Tegaserod pharmacokinetics are similar in patients with severe renal insufficiency and in healthy subjects.

Tegaserod (HTF 919), a selective 5-HT4 receptor partial agonist with promotile activity throughout the gastrointestinal tract, is in development for the treatment of irritable bowel syndrome. In an open-label, parallel-group study, the pharmacokinetics of a single 12-mg oral dose of tegaserod in patients with severe renal insufficiency requiring hemodialysis were compared with data obtained from healthy subjects matched for age, weight, height, and gender (n = 10, both). The pharmacokinetics of tegaserod were similar in both groups (AUC(0h-tz), ng.h/ml: 14.6 +/- 8.5 vs. 14.3 +/- 7.1; Cmax, ng/ml: 4.6 +/- 2.3 vs. 5.1 +/- 2.2; tmax, h: 1.0, for both). Tegaserod had similar tolerability in renally impaired patients and healthy volunteers, with adverse events largely related to the gastrointestinal pharmacological actions of the drug. Therefore, no dose adjustment of tegaserod is necessary for patients with renal insufficiency.

Does uremia protect against the demyelination associated with correction of hyponatremia during hemodialysis? A case report and literature review.

Rapid correction of chronic hyponatremia is known to cause demyelination syndromes, which are attributed to the rapid shift of water out of the brain. In uremic patients with hyponatremia, depending on the dialysate sodium concentration and delivered Kt/V, serum sodium levels may be rapidly corrected inadvertently during the hemodialysis (HD) session. It is not known whether uremic patients are as susceptible to the development of demyelination as patients with normal renal function. Since urea diffuses slowly across the blood-brain barrier, it can act as an effective osmole between plasma and the brain if levels are changed abruptly. During HD, blood urea levels drop suddenly and significantly and cerebral edema may develop (dialysis disequilibrium syndrome). This effect may counteract the fluid shift out of the brain during correction of hyponatremia. Therefore, theoretically, uremic patients may be less prone to develop demyelination. We present a patient with renal failure whose hyponatremia was corrected rapidly during HD to illustrate the potential problem. The patient tolerated rapid correction of hyponatremia without sustaining any neurologic damage. We performed a literature search looking for similar case reports and reviewed the scientific evidence behind the above hypothesis.

Single-dose pharmacokinetics and safety of pegylated interferon-alpha2b in patients with chronic renal dysfunction.

This study evaluates the pharmacokinetics and safety of pegylated interferon-alpha2b (PEG-Intron) following a single-dose subcutaneous injection into subjects with normal renal function, subjects with chronic renal impairment, and patients on hemodialysis. In this open-label, single-dose, parallel group study, subjects were divided into five groups according to their degree of renal function: four groups as defined by measured creatinine clearance and a fifth hemodialysis dependent group. They received 1 microg/kg PEG-Intron subcutaneously after a 10-hour fast. Pharmacokinetic and safety assessments were performed up to 168 hours postdose. Hemodialysis patients had a second PEG-Intron dose 12 hours prior to a hemodialysis session. PEG-Intron pharmacokinetic parameters (AUCtf, Cmax, and t1/2) increased progressively as CL(CR) declined. All subjects reported at least one adverse event, which were typical of those reported after alpha-interferon administration (e.g., flu-like symptoms, headache). Single-dose PEG-Intron administration to volunteers with normal renal function and chronic renal impairment was safe and well tolerated. In patients with CL(CR) < 30 ml/min, AUCand Cmax values were increased 90% compared with controls, while half-life was increased by up to 40% over controls. Based on the relationship between PEG-Intron apparent clearance and CL(CR), renal clearance accountsfor less than half of its total clearance. Hemodialysis did not affect PEG-Intron apparent clearance.

Intravenous and subcutaneous weight-based dosing of the low molecular weight heparin tinzaparin (Innohep) in end-stage renal disease patients undergoing chronic hemodialysis.

BACKGROUND: Patients with end-stage renal disease are subject to a broad range of thrombotic complications. Low molecular weight heparins (LMWHs) are effective antithrombotic agents; however, they are cleared largely by renal mechanisms, raising uncertainty about their use in renally impaired patients. METHODS: Twelve chronic hemodialysis subjects were administered two single doses of the LMWH tinzaparin, 75 IU/kg, 2 weeks apart: subcutaneously (SC) on an off-dialysis day and intravenously (IV) just before dialysis. RESULTS: Mean maximal anti-factor Xa (anti-Xa) activity was 0.33 IU/mL 4.0 hours after SC administration and 1.33 IU/mL 0.25 hours after IV administration. Anti-Xa half-lives were 3.89 and 2.31 hours, respectively. Anti-Xa activity returned to baseline within 24 hours of administration by either route. Consistent with population pharmacokinetic analyses of clinical study subjects with severe renal impairment, anti-Xa clearance after tinzaparin administration was reduced 28% relative to subjects with normal renal function. All 12 study subjects completed hemodialysis without requiring additional anticoagulation. One subject had minimal clotting in the dialyzer drip chamber, and one subject had mild prolonged bleeding at the vascular access site after dialysis needle removal. No major bleeding events occurred. CONCLUSION: Tinzaparin, 75 IU/kg, SC on an off-dialysis day and IV just before dialysis is well tolerated in chronic hemodialysis patients. The weight-based regimen of 75 IU/kg IV just before dialysis provides adequate anticoagulation. SC weight-based dosing on off-dialysis days is a feasible regimen for further clinical thromboprophylaxis efficacy studies in hemodialysis patients. The risk for clinical overdose in severely renally impaired patients using this weight-based regimen of tinzaparin is unlikely.

Randomized, controlled trial of darbepoetin alfa for the treatment of anemia in hemodialysis patients.

BACKGROUND: Darbepoetin alfa (Aranesp; Amgen, Thousand Oaks, CA) is a new erythropoiesis-stimulating protein with a threefold longer terminal half-life than recombinant human erythropoietin (epoetin) in patients with chronic kidney disease (CKD). The purpose of this randomized, double-blind, noninferiority study is to determine whether darbepoetin alfa is as effective as epoetin for the treatment of anemia in hemodialysis patients when administered at a reduced dosing frequency. METHODS: Patients receiving epoetin therapy were randomized to continue epoetin administered intravenously (IV) three times weekly (n = 338) or change to darbepoetin alfa administered IV once weekly (n = 169). The dose of darbepoetin alfa or epoetin was individually titrated to maintain hemoglobin concentrations within -1.0 to +1.5 g/dL (-10 to +15 g/L) of patients' baseline values and within a range of 9.0 to 13.0 g/dL (90 to 130 g/L) for up to 28 weeks (20-week dose-titration period followed by an 8-week evaluation period). The primary end point was change in hemoglobin level between baseline and the evaluation period (weeks 21 to 28). RESULTS: Mean changes in hemoglobin levels from baseline to the evaluation period were 0.24 +/- 0.10 (SE) g/dL (2.4 +/- 1.0 g/L) in the darbepoetin alfa group and 0.11 +/- 0.07 g/dL (1.1 +/- 0.7 g/L) in the epoetin group, a difference of 0.13 g/dL (95% confidence interval [CI], -0.08 +/- 0.33 [1.3 g/L; 95% CI, -0.8 to 3.3]). This difference was not statistically significant or clinically relevant despite the reduced frequency of darbepoetin alfa administration. The safety profile of darbepoetin alfa was similar to that of epoetin, and no antibody formation to either treatment was detected. CONCLUSION: These results show that darbepoetin alfa maintains hemoglobin concentrations as effectively and safely as epoetin in patients with CKD, but with a reduced dosing frequency.