Sevelamer carbonate lowers serum phosphorus effectively in haemodialysis patients: a randomized, double-blind, placebo-controlled, dose-titration study.

BACKGROUND: Hyperphosphataemia in patients with advanced chronic kidney disease (CKD) is associated with adverse outcomes, including vascular calcification and higher mortality rates. While phosphate lowering is an integral aspect of CKD management, the efficacy and safety of phosphate binders in a contemporary cohort of Chinese haemodialysis patients (who have different genetics and dietary patterns than other populations) has not been previously described. Moreover, sparse data are available on strategies for optimal dose titration when transitioning from a calcium-based to a polymer-based phosphate binder. METHODS: This randomized, double-blind, dose-titration study compared sevelamer carbonate (starting dose 800 mg three times daily) with placebo over 8 weeks' duration in Chinese CKD patients on haemodialysis. Patients were required to be using calcium-based binders prior to study start. RESULTS: In all, 205 patients were randomized (sevelamer, n = 135; placebo, n = 70); mean age was 48.6 years, 61% were male and the mean time on dialysis was 4.4 years. The mean serum phosphorus decreased significantly in patients treated with sevelamer carbonate [change -0.69 ± 0.64 mmol/L (-2.14 ± 1.98 mg/dL)] but remained persistently elevated with placebo [change -0.06 ± 0.57 mmol/L (-0.19 ± 1.76 mg/dL)] (P < 0.0001). When compared with placebo, sevelamer carbonate treatment resulted in statistically significant greater mean reductions from baseline in serum total (-17.1 versus -3.3%) and low-density lipoprotein cholesterol (-33.5 versus-7.6%) (P < 0.0001 for both). Sevelamer carbonate was well tolerated with 96% adherence compared with 97% adherence in the placebo arm. Overall, adverse events experienced by patients in the sevelamer carbonate and placebo treatment groups were similar and consistent with their underlying renal disease. CONCLUSIONS: This study demonstrated that hyperphosphataemia developed quickly following the cessation of phosphate binders and remained persistently elevated in end-stage CKD in the placebo-treated group. Gradually titrating up sevelamer carbonate from an initial dose of 2.4 g/day to an average daily dose of 7.1 ± 2.5 g/day was well tolerated, safe and efficacious in contemporary Chinese haemodialysis patients.

Converting to doxercalciferol capsules from intravenous paricalcitol or doxercalciferol.

OBJECTIVE: The purpose of the 2 studies presented in this article was to determine the clinically appropriate dose of doxercalciferol capsules that is required to maintain similar intact parathyroid hormone control when converting from intravenous (IV) paricalcitol or doxercalciferol. DESIGN: Both studies were multicenter, open-label, randomized designs comprising the following 3 periods: a screening period, a 5-week run-in period, and a 5-week treatment period. SETTING: Dialysis centers in the United States. PATIENTS: Patients with stage 5 chronic kidney disease receiving dialysis 3 times weekly for a minimum of 6 months and with recent intact parathyroid hormone measurements between 15.9 and 63.7 pmol/L (150 to 600 pg/mL) were included. INTERVENTION: After a 5-week fixed-dose IV paricalcitol or doxercalciferol run-in period, subjects were randomized to doxercalciferol capsules for the 5-week treatment period. Conversion factors for the paricalcitol study were 0.5, 1.0, and 1.5 times the current paricalcitol dose. Conversion factors for the doxercalciferol study were 1.0, 1.5, and 2.0 times the current doxercalciferol injection dose. RESULTS: The predicted conversion factor for paricalcitol injection to doxercalciferol capsules was 0.92, whereas the factor for doxercalciferol injection to doxercalciferol capsules was 1.49. No statistically significant changes in serum calcium and phosphorus levels were found in either study. The nature of adverse events was consistent with the administration of an active vitamin D therapy to patients with chronic kidney disease receiving dialysis. CONCLUSION: The studies demonstrate patients on dialysis can be safely and effectively converted from IV paricalcitol or doxercalciferol to oral doxercalciferol.

Results of a randomized crossover study comparing once-daily and thrice-daily sevelamer dosing.

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 x 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 x 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.

Novel dosage forms and regimens for sevelamer-based phosphate binders.

Sevelamer, a nonabsorbed, calcium- and metal-free dietary phosphate binder, consists of a polyallylamine polymer backbone with a cationic charge that shows a high capacity for binding anionically charged compounds such as phosphate. The currently licensed form of sevelamer, Renagel, exists as sevelamer hydrochloride, which disassociates in the acidic environment of the stomach and early gastrointestinal tract, exchanging the chloride ions attached to the polymer backbone for phosphate ions. The resulting absorption of these chloride ions has been reported to be accompanied by a reduction in serum levels of bicarbonate in some patients. To minimize the possibility of this effect, a new salt form of sevelamer has been developed in which carbonate replaces the chloride counter ion, thereby providing a source of buffer. The majority of phosphate binders exist only in tablet form and are dosed three times per day with meals. Genzyme has developed sevelamer carbonate in tablet form and also as a powder formulation that can be taken after mixing with water. This allows for an alternate and potentially more palatable way of dosing. Preliminary data exist suggesting that once daily dosing with sevelamer hydrochloride tablets provides similar phosphate control to three times daily dosing. By providing novel dosage forms and regimens for sevelamer-based phosphate binders, Genzyme will be providing patients and health care providers additional choices and flexibility in controlling phosphorus levels in chronic kidney disease. This should translate to increased compliance and improved rates of phosphate control.

Preclinical and clinical development of deferitrin, a novel, orally available iron chelator.

Deferitrin, a novel, orally available iron chelator, is in the early stage of clinical development for the treatment of chronic iron overload due to transfusional therapy. Preclinical pharmacology studies demonstrate iron excretion largely by the fecal route. Initial clinical studies have shown deferitrin to be well absorbed. Further clinical studies are ongoing to determine the efficiency and safety of deferitrin.