Results of a Randomized Crossover Study Comparing Once-Daily and Thrice-Daily Sevelamer Dosing
2006; Elsevier BV; Volume: 48; Issue: 3 Linguagem: Inglês
10.1053/j.ajkd.2006.05.026
ISSN1523-6838
AutoresD Fischer, Kenneth Cline, Melissa A. Plone, Maureen Dillon, Steven K. Burke, Andrew T. Blair,
Tópico(s)Dialysis and Renal Disease Management
ResumoBackground: Patients with renal failure require complex regimens of renal replacement therapies and medications, including ingestion of phosphate-binding agents 3 times daily. Previous studies suggested that sevelamer may provide extended phosphate binding and be effective with once-daily dosing, thus simplifying the phosphate-binder regimen. Methods: Twenty-four patients were enrolled in this study, 21 of whom were randomly assigned to sevelamer administration at their previously prescribed dose, either once daily with the largest meal or thrice daily with meals, with crossover to the other regimen after 4 weeks. Eighteen patients completed both treatment periods. The primary efficacy measure for which the study was powered is comparison of the effect of once-daily versus standard thrice-daily sevelamer dosing on serum phosphorus level control, determined by using equivalence testing. Secondary efficacy measures are the effects of the 2 regimens on serum calcium level corrected for albumin level; calcium × phosphorus product; albumin; intact parathyroid hormone; total, low-density lipoprotein, high-density lipoprotein, and non–high-density lipoprotein cholesterol; and triglyceride levels. Results: Once-daily sevelamer was as effective as thrice-daily dosing of sevelamer in controlling serum phosphorus, calcium, calcium × phosphorus product, serum albumin, and serum lipid levels. Bioequivalence was not shown for intact parathyroid hormone, likely because of high variability. Mean serum phosphorus levels were 4.6 ± 0.3 mg/dL (1.49 ± 0.10 mmol/L) during thrice-daily dosing and 5.0 ± 0.3 mg/dL (1.61 ± 0.10 mmol/L) during once-daily dosing. The average prescribed dose of sevelamer during both treatment regimens was 6.7 ± 2.4 g. Routine laboratory measures were similar in the 2 groups. Both regimens were well-tolerated. Conclusion: Despite concerted patient-directed educational efforts, phosphorus level control in patients with renal failure is suboptimal and contributes to increased mortality risk. Once-daily sevelamer could simplify these regimens and encourage medication compliance, perhaps improving hyperphosphatemia management. Background: Patients with renal failure require complex regimens of renal replacement therapies and medications, including ingestion of phosphate-binding agents 3 times daily. Previous studies suggested that sevelamer may provide extended phosphate binding and be effective with once-daily dosing, thus simplifying the phosphate-binder regimen. Methods: Twenty-four patients were enrolled in this study, 21 of whom were randomly assigned to sevelamer administration at their previously prescribed dose, either once daily with the largest meal or thrice daily with meals, with crossover to the other regimen after 4 weeks. Eighteen patients completed both treatment periods. The primary efficacy measure for which the study was powered is comparison of the effect of once-daily versus standard thrice-daily sevelamer dosing on serum phosphorus level control, determined by using equivalence testing. Secondary efficacy measures are the effects of the 2 regimens on serum calcium level corrected for albumin level; calcium × phosphorus product; albumin; intact parathyroid hormone; total, low-density lipoprotein, high-density lipoprotein, and non–high-density lipoprotein cholesterol; and triglyceride levels. Results: Once-daily sevelamer was as effective as thrice-daily dosing of sevelamer in controlling serum phosphorus, calcium, calcium × phosphorus product, serum albumin, and serum lipid levels. Bioequivalence was not shown for intact parathyroid hormone, likely because of high variability. Mean serum phosphorus levels were 4.6 ± 0.3 mg/dL (1.49 ± 0.10 mmol/L) during thrice-daily dosing and 5.0 ± 0.3 mg/dL (1.61 ± 0.10 mmol/L) during once-daily dosing. The average prescribed dose of sevelamer during both treatment regimens was 6.7 ± 2.4 g. Routine laboratory measures were similar in the 2 groups. Both regimens were well-tolerated. Conclusion: Despite concerted patient-directed educational efforts, phosphorus level control in patients with renal failure is suboptimal and contributes to increased mortality risk. Once-daily sevelamer could simplify these regimens and encourage medication compliance, perhaps improving hyperphosphatemia management. PATIENTS WITH RENAL failure have many comorbidities, requiring a complex regimen of renal replacement therapies and medications to sustain life. Disturbances in phosphorus metabolism mandate that nearly all hemodialysis patients use a phosphate-binding agent 3 times daily with meals to decrease intestinal absorption of dietary phosphate. The inconvenience of a thrice-daily dosing schedule was cited as having a role in patients’ poor adherence to phosphate-binding regimens.1Tomasello S. Dhupar S. Sherman R.A. Phosphate binders, K/DOQI guidelines, and compliance The unfortunate reality.Dial Transplant. 2004; 33 (291): 238-241Google Scholar, 2Cleary D.J. Matzke G.R. Alexander A.C.M. Joy M.S. Medication knowledge and compliance among patients receiving long-term dialysis.Am J Health Syst Pharm. 1995; 52: 1895-1900PubMed Google Scholar Studies suggested that patients may fail to take 18% to 20% or more of their prescribed phosphate binders, severely limiting treatment efficacy.1Tomasello S. Dhupar S. Sherman R.A. Phosphate binders, K/DOQI guidelines, and compliance The unfortunate reality.Dial Transplant. 2004; 33 (291): 238-241Google Scholar It was reported that despite routine use of phosphate binders, as many as 60% of hemodialysis patients have hyperphosphatemia,3Block G.A. Port F.K. Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients Recommendations for a change in management.Am J Kidney Dis. 2000; 35: 1226-1237Abstract Full Text Full Text PDF PubMed Scopus (573) Google Scholar which is associated with secondary hyperparathyroidism, metastatic calcification, and elevated mortality risk,4Block G.A. Hulbert-Shearon T.E. Levin N.W. Port F.K. Association of serum phosphorus and calcium × phosphate product with mortality risk in chronic hemodialysis patients A national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2120) Google Scholar, 5Ganesh S.K. Stack A.G. Levin N.W. Hulbert-Shearon T. Port F.K. Association of elevated serum PO(4), Ca × PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.J Am Soc Nephrol. 2001; 12: 2131-2138Crossref PubMed Scopus (1520) Google Scholar, 6Block G.A. Klassen P.S. Lazarus J.M. Ofsthun N. Lowrie E.G. Chertow G.M. Mineral metabolism, mortality and morbidity in maintenance hemodialysis.J Am Soc Nephrol. 2004; 15: 2208-2218Crossref PubMed Scopus (2216) Google Scholar, 7Kestenbaum B. Sampson J.N. Rudser K.D. et al.Serum phosphate levels and mortality risk among people with chronic kidney disease.J Am Soc Nephrol. 2005; 16: 520-528Crossref PubMed Scopus (953) Google Scholar testifying to the challenge of mineral management and poor adherence to phosphate-binder prescriptions. Sevelamer is a cationic hydrogel phosphate-binding polymer with a high binding capacity for negatively charged dietary phosphate ions. It is hypothesized that sevelamer may adhere to the anionic mucous lining of the gastrointestinal tract. As a result, transit time of sevelamer through the intestine may be longer compared with other binders, providing an extended period of phosphate binding, and thus require less frequent dosing. This study tested the hypothesis that sevelamer may need to be dosed only once daily with the largest meal to attain effective phosphorus control. Primary study objectives are to evaluate the equivalency of once-daily sevelamer dosing with the largest meal and standard thrice-daily sevelamer dosing with meals on serum phosphorus level control in hemodialysis patients and evaluate safety and tolerability. Secondary study objectives are to evaluate the equivalency of once-daily sevelamer dosing with the largest meal and standard thrice-daily sevelamer dosing on the following laboratory parameters: serum calcium level corrected for albumin level; calcium × phosphorus product; albumin; intact parathyroid hormone (iPTH); total, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and non-HDL cholesterol; and triglycerides. This study was conducted from August 2003 through May 2004. Twenty-four adults receiving maintenance hemodialysis at 2 nephrology centers in the United States (Kidney and Hypertension Center, Cincinnati, OH, and Renal Care Group, Olympia Fields, IL) were enrolled in this study. All patients provided informed consent to participate. Patients were eligible for the study if they had a life expectancy of at least 12 months, had received hemodialysis 3 times weekly for 3 months or longer, and were maintained on sevelamer in a daily dose of 9,600 mg or less as their only phosphate binder, with serum phosphorus concentrations at the last 2 measurements between 3.0 and 6.5 mg/dL (0.97 and 2.10 mmol/L). Patients were excluded from the study if they had active bowel obstruction, dysphagia, swallowing disorders, severe gastrointestinal motility disorders, active ethanol or drug abuse (excluding tobacco), need for antiarrhythmic or antiseizure medications to control these conditions, poorly controlled diabetes mellitus or hypertension, active vasculitis, active malignancy other than basal-cell carcinoma, human immunodeficiency virus infection, or any clinically significant unstable medical condition as judged by the investigator. Before initiation at each site, the protocol was reviewed and approved by an institutional review board. This research was carried out in accordance with the International Conference on Harmonization Good Clinical Practice guidelines and legislations.8International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use: E6(R1): Good Clinical Practice: Consolidated Guideline. Available at: www.ich.org. Accessed April 21, 2006Google Scholar This was a randomized, crossover, open-label study. The study consisted of 4 periods (Fig 1). Enrolled patients entered a 1-week screening period (week −3) in which eligibility was determined. Eligible patients next entered a 2-week run-in period, during which the investigator maintained a stable dose of sevelamer and vitamin D therapy and up to three 24-hour dietary recalls were collected.9Posner B.M. Borman C.L. Morgan J.L. Borden W.S. Ohls J.C. The validity of a telephone-administered 24-hour dietary recall methodology.Am J Clin Nutr. 1982; 36: 546-553PubMed Scopus (89) Google Scholar Eligible patients then were assigned randomly (based on computer-generated random numbers) to 1 of the 2 treatment sequences: (1) sevelamer dosed once daily with the largest meal for 4 weeks, followed by standard sevelamer thrice-daily dosing with meals for 4 weeks (once-daily/thrice-daily sequence); or (2) sevelamer dosed thrice daily with meals for 4 weeks, followed by sevelamer once-daily dosing with the largest meal for 4 weeks (thrice-daily/once-daily sequence). Randomization was stratified by site to ensure equal allocation of patients within sites. Patients were instructed to maintain a fixed daily dose throughout both treatment periods based on the most recently prescribed sevelamer dose before screening. Patients were not to be started on treatment with vitamin D or lipid-lowering medications, and if prescribed these medications before study initiation, the dose was to be maintained for the duration of the study. During treatment period 1, patients returned for 1 follow-up visit during weeks 1 and 2 and 2 follow-up visits during weeks 3 and 4. Blood samples were collected just before dialysis at all visits. Three 24-hour dietary recalls were collected during weeks 3 and 4.9Posner B.M. Borman C.L. Morgan J.L. Borden W.S. Ohls J.C. The validity of a telephone-administered 24-hour dietary recall methodology.Am J Clin Nutr. 1982; 36: 546-553PubMed Scopus (89) Google Scholar At the second week-4 visit, the patient was switched to the other dosing regimen. During treatment period 2, patients returned for follow-up visits on the same schedule. All efficacy analyses were performed using data from patients who completed both study treatment periods (n = 18). The primary efficacy variable was time-weighted average of serum phosphorus levels from the last 2 weeks of each treatment period (up to 4 measures obtained during weeks 3 and 4 or weeks 7 and 8). Secondary efficacy measures included serum calcium level corrected for albumin level; calcium × phosphorus product; albumin; iPTH; total, LDL, HDL, and non-HDL cholesterol; and triglyceride levels based on time-weighted averages of laboratory values for each parameter from the last 2 weeks of each treatment period (up to 4 measures per parameter). Measurements were not carried forward. Equivalence was assessed based on the 5% two 1-sided equivalence test10Schuirmann D.J. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability.J Pharmacokinet Biopharm. 1987; 15: 657-680Crossref PubMed Scopus (2116) Google Scholar of the ratio of geometric means of the thrice-daily time-weighted means to the once-daily time-weighted means for each laboratory parameter. This test requires a 90% confidence interval for the ratio to be within the interval (0.80 to 1.25). An analysis of variance model for the time-weighted means on the log-transformed scale had factors for dosing regimen, sequence, and period as fixed effects and subject within sequence as the random effect and was used to estimate the SE of the difference in least-squares means, which, when back-transformed to the original scale, provided estimates of the ratio of geometric means between the 2 treatment regimens and the confidence interval. Sample-size calculations showed that 7 assessable patients per sequence (once-daily/thrice-daily versus thrice-daily/once-daily sequence) for a total of 14 patients were required to achieve 90% power to detect equivalence based on a 5% two 1-sided equivalence test (ie, reject both null hypotheses that the ratio of the geometric means of thrice-daily time-weighted means to once-daily time-weighted means is 1.25 each at the 5% level), assuming that the expected ratio of means is 1 and the within-subject mean square error from a crossover analysis of variance is 0.0265. The mean square error used in this calculation was derived from a simulation based on serum phosphorus levels during a steady-state phase of a prior study because no directly applicable data were available. Given an expected dropout rate of 20% and the need to rely on simulated data for the purpose of determining sample size, a total of 24 patients were planned to be randomly assigned to 1 of the 2 treatment sequences. Patient compliance with study medication was calculated as the number of tablets ingested in the period divided by the total number of tablets prescribed in the period and multiplied by 100. Compliance was summarized by dosing regimen overall and for each treatment period. Analysis of variance models were used to test equality in compliance between treatment groups and treatment sequences. Dietary intake was assessed by using a dietary 24-hour recall method (University of South Carolina). Relevant dietary parameters were summarized overall and by treatment sequence, and differences in nutrient intake were assessed by using a Proc Mixed procedure in SAS (SAS Institute Inc, Cary, NC). Safety was evaluated on the basis of adverse experiences (reported or observed) and changes in laboratory values. All statistical analyses were performed using SAS, version 8.02, in a validated environment. Twenty-four patients enrolled in the study. Three patients were determined to be ineligible. Twenty-one patients were randomly assigned and entered the treatment period (Fig 2). As listed in Table 1, 13 of 18 patients (72.2%) were men and 5 patients (27.8%) were women, with a mean age of 63 years. Blacks comprised 61.1% of the patient population, with 38.9% whites. Half the patients had diabetes (50.0%), and all except 1 patient had hypertension (94.4%).Table 1Demographic CharacteristicsTreatment SequenceVariableOverall (N = 18)Thrice-Daily/Once-Daily (n = 9)Once-Daily/Thrice-Daily (n = 9)Age (y) Mean ± SD63.4 ± 16.666.0 ± 17.360.9 ± 16.4 Median65.573.059.0 Range33-8638-8633-83Sex Men13 (72.2)7 (77.8)6 (66.7) Women5 (27.8)2 (22.2)3 (33.3)Race White7 (38.9)3 (33.3)4 (44.4) Black11 (61.1)6 (66.7)5 (55.6)Diabetes Yes9 (50.0)5 (55.6)4 (44.4) No9 (50.0)4 (44.4)5 (55.6)Hypertension Yes17 (94.4)9 (100.0)8 (88.9) No1 (5.6)0 (0.0)1 (11.1)Primary cause of chronic renal failure Hypertension7 (38.9)4 (44.4)3 (33.3) Glomerulonephritis2 (11.1)1 (11.1)1 (11.1) Diabetes7 (38.9)3 (33.3)4 (44.4) Polycystic kidneys1 (5.6)0 (0.0)1 (11.1) Interstitial nephritis1 (5.6)1 (11.1)0 (0.0)Urea reduction ratio (%) Mean ± SD72.6 ± 4.271.7 ± 3.173.4 ± 5.1NOTE. Values expressed as number (percent) unless noted otherwise. Open table in a new tab NOTE. Values expressed as number (percent) unless noted otherwise. The 3 most common primary causes of chronic renal failure were hypertension (38.9%), diabetes (38.9%), and glomerulonephritis (11.1%; Table 1). Patients had been on dialysis therapy for an average of 2.9 years. Average prescribed time on dialysis was 3.8 hours per session, and average dialysate bath calcium concentration was 2.5 mEq/L. Two patients (11.1%) had received a kidney transplant and 1 patient (5.6%) had undergone parathyroidectomy. The majority of patients (83.3%) currently were receiving vitamin D therapy, with average vitamin D use for 2.4 years. Average time patients had most recently been on sevelamer therapy was 0.7 years. Mean urea reduction ratio was 72.6%. Baseline laboratory tests that were consistent with patients receiving hemodialysis are listed in Table 2.Table 2Baseline Laboratory ValuesVariableOverall (N = 18)Treatment SequenceThrice-Daily/Once-Daily (n = 9)Once-Daily/Thrice-Daily (n = 9)Phosphorus (mg/dL) Mean ± SD4.9 ± 1.05.1 ± 1.14.7 ± 0.9 Median5.05.05.0Calcium (mg/dL) Mean ± SD9.6 ± 0.79.5 ± 0.79.6 ± 0.6 Median9.49.39.6Calcium × phosphorus product (mg2/dL2) Mean ± SD47.0 ± 11.149.0 ± 12.445.0 ± 10.1 Median45.949.543.7Albumin (g/dL) Mean ± SD3.9 ± 0.33.9 ± 0.23.8 ± 0.3 Median3.93.93.9iPTH (pg/mL) Mean ± SD242.4 ± 175.4312.4 ± 226.9172.4 ± 53.6 Median192.0246.0187.0Total cholesterol (mg/dL) Mean ± SD141.3 ± 38.0126.0 ± 36.3156.7 ± 35.0 Median137.0122.0151.0LDL cholesterol (mg/dL) Mean ± SD66.8 ± 24.855.1 ± 23.677.2 ± 22.1 Median62.051.084.0HDL cholesterol (mg/dL) Mean ± SD38.7 ± 10.038.4 ± 10.939.0 ± 9.8 Median36.033.038.0Non-HDL cholesterol (mg/dL) Mean ± SD102.6 ± 35.687.6 ± 33.2117.7 ± 32.9 Median100.090.0108.0Triglycerides (mg/dL) Mean ± SD189.2 ± 131.3175.1 ± 168.6203.3 ± 88.3 Median164.5146.0195.0NOTE. To convert phosphorus in mg/dL to mmol/L, multiply by 0.3229; calcium in mg/dL to mmol/L, multiply by 0.2495; albumin in g/dL to g/L, multiply by 10; iPTH in pg/mL to ng/L, multiply by 1; total, LDL, and HDL cholesterol in mg/dL to mmol/L, multiply by 0.02586; triglycerides in mg/dL to mmol/L, multiply by 0.01129. Open table in a new tab NOTE. To convert phosphorus in mg/dL to mmol/L, multiply by 0.3229; calcium in mg/dL to mmol/L, multiply by 0.2495; albumin in g/dL to g/L, multiply by 10; iPTH in pg/mL to ng/L, multiply by 1; total, LDL, and HDL cholesterol in mg/dL to mmol/L, multiply by 0.02586; triglycerides in mg/dL to mmol/L, multiply by 0.01129. Mean values of nutritional parameters, determined by dietary intake assessment using a 24-hour recall method,9Posner B.M. Borman C.L. Morgan J.L. Borden W.S. Ohls J.C. The validity of a telephone-administered 24-hour dietary recall methodology.Am J Clin Nutr. 1982; 36: 546-553PubMed Scopus (89) Google Scholar indicated that patients’ diets during the run-in period and each treatment regimen were similar for each treatment sequence group. There were no significant differences in dietary intake between treatment regimens for patients who completed both treatment periods (n = 18), suggesting that efficacy results were not influenced by dietary changes (Table 3).Table 3Dietary Intake During Randomized Treatment PeriodsParameterThrice Daily (N = 18)Once Daily (N = 18)P⁎Treatment P obtained from a mixed-effect model with treatment, period, and sequence as fixed effects and subject within sequence as a random effect.Phosphorus (mg/d)882.5 ± 395.2815.1 ± 273.50.491Calcium (mg/d)563.1 ± 373.2437.3 ± 188.60.104Vitamin D (μg/d)3.2 ± 2.03.2 ± 1.90.970Total energy (kcal/d)1,520.9 ± +641.11,499.3 ± 543.10.839Total protein (g/d)64.8 ± 28.562.3 ± 27.60.758Cholesterol (mg/d)240.9 ± 154.2267.1 ± 152.20.529Carbohydrate (g/d)182.6 ± 65.4178.2 ± 59.10.690 Treatment P obtained from a mixed-effect model with treatment, period, and sequence as fixed effects and subject within sequence as a random effect. Open table in a new tab During the run-in period, mean treatment compliance was 89% for the 18 patients who completed both treatment periods. Overall treatment compliance was slightly greater for the once-daily dosing regimen (97% versus 92% for the once-daily and thrice-daily treatments, respectively), but this difference did not reach statistical significance (P = 0.115). This trend was observed in both treatment sequences. Mean prescribed daily dose of sevelamer was 6.8 ± 2.4 g during the run-in period. Average prescribed dose of sevelamer during both treatment regimens was 6.7 ± 2.4 g. No patient changed sevelamer daily dose during the randomized treatment period. The majority of patients (14 patients) ingested the once-daily dose with dinner, with only 3 patients ingesting it with lunch and 1 patient ingesting it with breakfast. As listed in Table 4, once-daily sevelamer dosing with the largest meal was equivalent to standard thrice-daily dosing for controlling serum phosphorus levels, the primary end point in this study. Once-daily sevelamer dosing also was equivalent to standard thrice-daily dosing with respect to values for serum calcium; calcium × phosphorus product; albumin; total, LDL, HDL, and non-HDL cholesterol; and triglycerides. Bioequivalence between the 2 dosing regimens was not shown for iPTH levels, likely because of high variability.Table 4Equivalence AnalysisLaboratory ParameterThrice Daily (N = 18)Once Daily (N = 18)Least Squares Mean Ratio90% Confidence IntervalMean ± SEMedianMean ± SEMedianPhosphorus (mg/dL)4.6 ± 0.34.75.0 ± 0.35.00.920.83-1.01⁎The 90% confidence interval for the ratio is within the interval 0.8 to 1.25.Calcium (mg/dL)9.5 ± 0.29.49.4 ± 0.29.41.010.99-1.03⁎The 90% confidence interval for the ratio is within the interval 0.8 to 1.25.Calcium × phosphorus product (mg2/dL2)44.0 ± 2.844.747.3 ± 2.748.70.930.84-1.03⁎The 90% confidence interval for the ratio is within the interval 0.8 to 1.25.Albumin (g/dL)3.8 ± 0.13.93.8 ± 0.13.81.000.99-1.01⁎The 90% confidence interval for the ratio is within the interval 0.8 to 1.25.iPTH (pg/mL)216.8 ± 38.2227.0247.0 ± 40.8226.80.880.75-1.02Total cholesterol (mg/dL)132.5 ± 7.7131.4135.0 ± 7.8133.00.980.95-1.01⁎The 90% confidence interval for the ratio is within the interval 0.8 to 1.25.LDL cholesterol (mg/dL)58.1 ± 6.062.860.5 ± 5.459.70.960.89-1.04⁎The 90% confidence interval for the ratio is within the interval 0.8 to 1.25.HDL cholesterol (mg/dL)39.2 ± 2.440.039.8 ± 2.440.40.980.95-1.03⁎The 90% confidence interval for the ratio is within the interval 0.8 to 1.25.Non-HDL cholesterol (mg/dL)90.4 ± 7.893.692.5 ± 7.897.40.980.91-1.04⁎The 90% confidence interval for the ratio is within the interval 0.8 to 1.25.Triglycerides (mg/dL)148.4 ± 22.1162.8144.3 ± 24.0164.91.030.94-1.12⁎The 90% confidence interval for the ratio is within the interval 0.8 to 1.25.NOTE. To convert phosphorus in mg/dL to mmol/L, multiply by 0.3229; calcium in mg/dL to mmol/L, multiply by 0.2495; albumin in g/dL to g/L, multiply by 10; iPTH in pg/mL to ng/L, multiply by 1; total, LDL, and HDL cholesterol in mg/dL to mmol/L, multiply by 0.02586; triglycerides in mg/dL to mmol/L, multiply by 0.01129. The 90% confidence interval for the ratio is within the interval 0.8 to 1.25. Open table in a new tab NOTE. To convert phosphorus in mg/dL to mmol/L, multiply by 0.3229; calcium in mg/dL to mmol/L, multiply by 0.2495; albumin in g/dL to g/L, multiply by 10; iPTH in pg/mL to ng/L, multiply by 1; total, LDL, and HDL cholesterol in mg/dL to mmol/L, multiply by 0.02586; triglycerides in mg/dL to mmol/L, multiply by 0.01129. Average serum phosphorus levels during thrice-daily and once-daily dosing are shown by patient in Fig 3. The majority of patients maintained similar phosphorus levels regardless of treatment regimen; however, 1 patient’s serum phosphorus level increased substantially during once-daily treatment. During the randomized treatment period, 9 patients (42.9%) reported an adverse event during the thrice-daily regimen and 12 patients (57.1%) reported an adverse event during the once-daily regimen. The majority of reported treatment-emergent adverse events were mild to moderate in intensity. Gastrointestinal symptoms were the most frequently reported adverse event. Most were mild in intensity, and none led to discontinuation of sevelamer treatment. Seven of 21 patients (33.3%) in the safety analysis experienced a total of 15 serious adverse events during randomized treatment. All serious adverse events were deemed by the investigator not to be related to sevelamer. Routine laboratory measures were similar in the 2 groups. There were no clinically significant changes in values for laboratory parameters examined. One patient withdrew from the study because of hypophosphatemia during once-daily treatment that was possibly related to sevelamer. Hyperphosphatemia generally is difficult to control in patients with chronic kidney disease on dialysis therapy and is associated with a significant mortality risk.3Block G.A. Port F.K. Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients Recommendations for a change in management.Am J Kidney Dis. 2000; 35: 1226-1237Abstract Full Text Full Text PDF PubMed Scopus (573) Google Scholar, 4Block G.A. Hulbert-Shearon T.E. Levin N.W. Port F.K. Association of serum phosphorus and calcium × phosphate product with mortality risk in chronic hemodialysis patients A national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2120) Google Scholar, 5Ganesh S.K. Stack A.G. Levin N.W. Hulbert-Shearon T. Port F.K. Association of elevated serum PO(4), Ca × PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.J Am Soc Nephrol. 2001; 12: 2131-2138Crossref PubMed Scopus (1520) Google Scholar, 6Block G.A. Klassen P.S. Lazarus J.M. Ofsthun N. Lowrie E.G. Chertow G.M. Mineral metabolism, mortality and morbidity in maintenance hemodialysis.J Am Soc Nephrol. 2004; 15: 2208-2218Crossref PubMed Scopus (2216) Google Scholar, 7Kestenbaum B. Sampson J.N. Rudser K.D. et al.Serum phosphate levels and mortality risk among people with chronic kidney disease.J Am Soc Nephrol. 2005; 16: 520-528Crossref PubMed Scopus (953) Google Scholar Safe and effective medication regimens to decrease dietary phosphate absorption are critical to correcting mineral metabolism imbalances. Sevelamer dosed thrice daily with meals was shown to be safe and effective at decreasing serum phosphorus levels to less than the current targets of less than 5.5 mg/dL (<1.78 mmol/L) without adding excess calcium or promoting vascular calcification.11Chertow G.M. Burke S.K. Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.Kidney Int. 2002; 62: 245-252Crossref PubMed Scopus (1331) Google Scholar, 12National Kidney FoundationK/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease.Am J Kidney Dis. 2003; 42: S1-S201PubMed Google Scholar Results of this randomized crossover study indicate that both once-daily and thrice-daily sevelamer dosing were well tolerated. Overall, once-daily sevelamer dosing with the largest meal was found to provide control of serum phosphorus, calcium, and lipid profile values equivalent to that of standard thrice-daily sevelamer dosing. However, for some patients, once-daily dosing did not adequately control serum phosphorus levels. We acknowledge that once-daily dosing may not be ideal for all patients, but by providing alternate dosing regimens, we hope to provide additional choices and flexibility in controlling phosphorus levels for patients and health care providers. Adherence to phosphate-binding regimens in this study was high (97% versus 92% for once-daily and thrice-daily regimens, respectively). In general, patient adherence to phosphate-binding regimens is much poorer despite concerted patient-directed educational efforts. A systematic review of medication adherence found an inverse relationship between number of daily doses of a variety of medications and medication compliance, with compliance significantly greater for once-daily versus thrice-daily regimens.13Claxton A.J. Cramer J. Pierce C. A systematic review of the associations between dose regimens and medication compliance.Clin Ther. 2001; 23: 1296-1310Abstract Full Text PDF PubMed Scopus (1966) Google Scholar The high compliance in this study may be related to this being a well-controlled clinical trial of short duration. Therefore, the excellent compliance observed likely does not accurately reflect long-term compliance with each treatment regimen. The extended activity of unabsorbed sevelamer in the gut may be related to a prolonged transit time. One study showed that only 5.7% of an ingested dose was eliminated in human feces within the first 24 hours after administration, with greater than 50% of sevelamer elimination reached 24 to 48 hours after ingestion and greater than 99% elimination reached 8 days after ingestion.14Plone M.A. Petersen J.S. Rosenbaum D.P. Burke S.K. Sevelamer, a phosphate-binding polymer, is a non-absorbed compound.Clin Pharmacokinet. 2002; 41: 517-523Crossref PubMed Scopus (54) Google Scholar Sevelamer is a cationic hydrogel that may interact with the anionic mucous lining of the gastrointestinal tract. Studies to determine whether sevelamer is “mucoadhesive” are ongoing. Once-daily sevelamer dosing could simplify phosphate-binding therapy, potentially improving adherence to prescriptions of this important class of medications. Moreover, with a new powder formulation currently under development,15Duggal M.A. Hanus J.S. Zhorov D.P. et al.Novel dosage forms and regimens for sevelamer-based phosphate binders.J Ren Nutr. 2006; 16: 248-252Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar once-daily sevelamer dosing could dramatically decrease the pill burden for patients with chronic kidney disease, who often are administered multiple medications. Although these initial study results are very encouraging, the study was limited by the short duration of each treatment arm, small sample size, and that enrollment was restricted to patients already tolerating standard thrice-daily sevelamer dosing. Additional studies of a broader patient population are warranted to further evaluate simplified dosing strategies to improve management of hyperphosphatemia in patients with chronic kidney disease.
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