Biomedical subjects

Steven K Burke

Publications and source records attributed to Steven K Burke.

16 recordsLinked to original sources

PubMed2006

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.

Aged↗

PubMed2006

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.

Animals↗

PubMed2004

Decrease in thoracic vertebral bone attenuation with calcium-based phosphate binders in hemodialysis.

UNLABELLED: We performed a post hoc analysis of a 52-week randomized trial conducted in adult hemodialysis patients that compared the effects of calcium-based phosphate binders and sevelamer, a nonabsorbable polymer, on parameters of mineral metabolism and vascular calcification by electron beam tomography. In this analysis, we evaluated the relative effects of calcium and sevelamer on thoracic vertebral attenuation by CT and markers of bone turnover. Subjects randomized to calcium salts experienced a significant reduction in trabecular bone attenuation and a trend toward reduction in cortical bone attenuation, in association with higher concentrations of serum calcium, lower concentrations of PTH, and reduced total and bone-specific alkaline phosphatase. INTRODUCTION: In patients with chronic kidney disease, hyperphosphatemia is associated with osteodystrophy, vascular and soft tissue calcification, and mortality. Calcium-based phosphate binders are commonly prescribed to reduce intestinal phosphate absorption and to attenuate secondary hyperparathyroidism. Clinicians and investigators have presumed that, in hemodialysis patients, calcium exerts beneficial effects on bone. MATERIALS AND METHODS: We performed a post hoc analysis of a 52-week randomized trial conducted in adult hemodialysis patients that compared the effects of calcium-based phosphate binders and sevelamer, a nonabsorbable polymer, on parameters of mineral metabolism and vascular calcification by electron beam tomography. In this analysis, we evaluated the relative effects of calcium and sevelamer on thoracic vertebral attenuation by CT and markers of bone turnover. RESULTS AND CONCLUSIONS: The average serum phosphorus and calcium x phosphorus products were similar for both groups, although the average serum calcium concentration was significantly higher in the calcium-treated group. Compared with sevelamer-treated subjects, calcium-treated subjects showed a decrease in thoracic vertebral trabecular bone attenuation (p = 0.01) and a trend toward decreased cortical bone attenuation. More than 30% of calcium-treated subjects experienced a 10% or more decrease in trabecular and cortical bone attenuation. On study, sevelamer-treated subjects had higher concentrations of total and bone-specific alkaline phosphatase, osteocalcin, and PTH (p < 0.001). When used to correct hyperphosphatemia, calcium salts lead to a reduction in thoracic trabecular and cortical bone attenuation. Calcium salts may paradoxically decrease BMD in hemodialysis patients.

Aged↗

PubMed2004

Determinants of progressive vascular calcification in haemodialysis patients.

BACKGROUND: We determined recently that targeted treatment with calcium-based phosphate binders (calcium acetate and carbonate) led to progressive coronary artery and aortic calcification by electron beam tomography (EBT), while treatment with the non-calcium-containing phosphate binder, sevelamer, did not. Aside from the provision of calcium, we hypothesized that other factors might be related to the likelihood of progressive calcification in both or either treatment groups. METHODS: We explored potential determinants of progressive vascular calcification in 150 randomized study subjects who underwent EBT at baseline and at least once during follow-up (week 26 or 52). RESULTS: Among calcium-treated subjects, higher time-averaged concentrations of calcium, phosphorus and the calcium-phosphorus product were associated with more pronounced increases in EBT scores; no such associations were demonstrated in sevelamer-treated subjects. The relation between parathyroid hormone (PTH) and the progression of calcification was more complex. Lower PTH was associated with more extensive calcification in calcium-treated subjects, whereas higher PTH was associated with calcification in sevelamer-treated subjects. Serum albumin was inversely correlated with progression in aortic calcification. Sevelamer was associated with favourable effects on lipids, although the link between these effects and the observed attenuation in vascular calcification remains to be elucidated. CONCLUSION: Calcium-based phosphate binders are associated with progressive coronary artery and aortic calcification, especially when mineral metabolism is not well controlled. Calcium may directly or indirectly (via PTH) adversely influence the balance of skeletal and extraskeletal calcification in haemodialysis patients.

Aged↗

PubMed2004

Arterial calcification in chronic kidney disease.

Hyperphosphatemia is associated with soft-tissue calcification and bone disease. Nephrologists prescribe phosphate binders to decrease dietary phosphate absorption, reduce serum phosphorus concentrations, and minimize the risk for soft-tissue calcification and bone disease. Recent data suggest that the dose of calcium used as a phosphate binder may contribute to the risk for cardiovascular calcification. Chronic positive calcium balance from diet, dialysis, and calcium-based phosphate binders or intermittent hypercalcemia may favor precipitation of calcium and phosphate into tissues. Calcium suppresses parathyroid hormone (PTH) secretion and bone turnover, limiting the ability of bone to incorporate calcium and phosphorus. Sevelamer, a non-absorbed polymer, allows physicians to bind dietary phosphate and decrease serum phosphorus without unwanted absorption of metals or calcium or over-suppression of PTH. In a comparative trial, calcium-based phosphate binders were associated with progressive coronary artery and aortic calcification that was attenuated by sevelamer. The optimal phosphate binder is one that controls hyperphosphatemia prevents soft-tissue calcification and preserves bone health.

Arteries↗

PubMed2003

The effects of sevelamer and calcium acetate on proxies of atherosclerotic and arteriosclerotic vascular disease in hemodialysis patients.

BACKGROUND: We recently determined that in hemodialysis patients, the use of calcium salts to correct hyperphosphatemia led to progressive coronary artery and aortic calcification as determined by sequential electron beam tomography (EBT) while the use of the non-calcium-containing binder sevelamer did not. Whether the specific calcium preparation (acetate vs. carbonate) might influence the likelihood of progressive calcification was debated. METHODS: To determine whether treatment with calcium acetate was specifically associated with hypercalcemia and progressive vascular calcification, we conducted an analysis restricted to 108 hemodialysis patients randomized to calcium acetate or sevelamer and followed for one year. RESULTS: The reduction in serum phosphorus was roughly equivalent with both agents (calcium acetate -2.5 +/- 1.8 mg/dl vs. sevelamer -2.8 +/- 2.0 mg/dl, p = 0.53). Subjects given calcium acetate were more likely to develop hypercalcemia (defined as an albumin-corrected serum calcium > or =10.5 mg/dl) (36 vs. 13%, p = 0.015). Treatment with calcium acetate (mean 4.6 +/- 2.1 g/day - equivalent to 1.2 +/- 0.5 g of elemental calcium) led to a significant increase in EBT-determined calcification of the coronary arteries (mean change 182 +/- 350, median change +20, p = 0.002) and aorta (mean change 181 +/- 855, median change +73, p < 0.0001). These changes were similar in magnitude to those seen with calcium carbonate. There were no significant changes in calcification among sevelamer-treated subjects. CONCLUSION: Despite purported differences in safety and efficacy relative to calcium carbonate, calcium acetate led to hypercalcemia and progressive vascular calcification in hemodialysis patients.

Acetates↗

PubMed2003

Sevelamer hydrochloride prevents ectopic calcification and renal osteodystrophy in chronic renal failure rats.

BACKGROUND: Hyperphosphatemia is associated with severe complications, including ectopic calcification of soft tissues, secondary hyperparathyroidism, and renal osteodystrophy (ROD). Sevelamer hydrochloride is a nonabsorbed calcium- and metal-free phosphate binder that lowers serum phosphorus levels in hemodialysis patients. This study examined the efficacy of sevelamer in preventing ectopic calcification of soft tissues and ROD in adenine-induced renal failure rats. METHODS: Male, 12-week-old Wistar-Jcl rats were freely fed an adenine diet (0.75 g adenine in 100 g normal diet) for four weeks. After three weeks of the adenine diet, when serum phosphorus levels had significantly increased, the rats were freely fed a normal diet that contained 1% or 2% of sevelamer for another five weeks. Time course changes of serum levels of phosphorus, calcium, and parathyroid hormone (PTH) were measured. At the end of the study, calcium and phosphorus levels in the heart and aorta were measured, and the calcification of kidney, heart, aorta, and stomach were histopathologically examined. The severity of ROD was evaluated by a histopathologic and morphometric analysis of the femurs. RESULTS: Compared with the adenine controls (N = 10), the sevelamer-treated (1%, N = 6; and 2%, N = 10) groups of adenine-induced renal failure rats had reduced serum phosphorus, serum calcium x phosphorus product, and serum PTH levels. Moreover, in the treatment groups, sevelamer suppressed calcification of the aorta media, and also the osteoid volume, fibrosis volume, and porosity ratio of femurs. CONCLUSION: These results suggest that sevelamer treatment might contribute to the suppression of ectopic calcification and ROD.

Animals↗

PubMed2003

Sevelamer hydrochloride attenuates kidney and cardiovascular calcifications in long-term experimental uremia.

BACKGROUND: In chronic renal failure (CRF), hyperphosphatemia and an elevated calcium-phosphate product are associated with vascular calcification and increased cardiovascular morbidity and mortality. Previous data have demonstrated that 3-month treatment of uremic rats with sevelamer was associated with less nephrocalcinosis compared to calcium carbonate (CaCO3), despite similar control of serum phosphorus, calcium-phosphorus product (Ca x P product), and secondary hyperparathyroidism. There was no evidence of aortic calcification after 3 months of uremia (J Am Soc Nephrol 13:2299-2308, 2002). The present studies explore the influence of sevelamer and CaCO3 on cardiovascular and kidney calcifications in long-term experimental uremia over 6 months. METHODS: Normal and 5/6 nephrectomized rats (U) were fed a high phosphorus (HP) diet for 6 months. Two phosphate binders, CaCO3 and sevelamer, were administered and their influence on hyperphosphatemia, secondary hyperparathyroidism, kidney/myocardial/aortic calcification, and renal function was compared. RESULTS: All uremic rats began the study with the same degree of renal failure. Sevelamer was as effective as CaCO3 in reducing serum phosphorus, Ca x P product, and attenuating secondary hyperparathyroidism. Despite similar serum cholesterol levels, rats in the U-HP + sevelamer group had markedly lower calcium deposition in the myocardium and aorta (myocardium, 72 +/- 4 microg/g wet tissue; aorta, 736 +/- 156 microg/g wet tissue) compared to rats in either the U-HP + CaCO3 group (myocardium, 179 +/- 48, P < 0.05; aorta, 1308 +/- 343, P < 0.05) or the U-HP group (myocardium, 98 +/- 10, NS; aorta, 2150 +/- 447, P < 0.05). Dual immunohistochemical analysis for calcium and endothelial cell markers demonstrated that myocardial calcium deposition was intravascular within capillaries. Furthermore, calcium deposition in the kidney of uremic rats treated with sevelamer (582 +/- 111 microg/g wet tissue) was lower than that found in uremic rats treated with CaCO3 (1196 +/- 180 microg/g wet tissue). Sevelamer-treated rats had less deterioration in renal function with an associated lower serum creatinine, higher creatinine clearance, and less proteinuria. There was no difference in overall mortality between the three experimental groups. CONCLUSION: In long-term experimental CRF, in addition to controlling serum phosphorus and secondary hyperparathyroidism as efficiently as CaCO3, treatment with the phosphate-binder sevelamer attenuates vascular and kidney calcification.

Animals↗

PubMed2003

Meta-analysis of the effect of sevelamer on phosphorus, calcium, PTH, and serum lipids in dialysis patients.

Hyperphosphatemia and dyslipidemia are common clinically significant conditions in end-stage renal disease (ESRD). Hyperphosphatemia management is essential; however, use of calcium-based phosphate binder has been associated with elevated risk of cardiac calcification in ESRD, increasing risks for cardiovascular disease and death. An alternative to calcium-based phosphate binders is sevelamer hydrochloride, a calcium-free, metal-free, nonabsorbed polymer that binds phosphate effectively. We conducted a meta-analysis on the effects of sevelamer hydrochloride on parameters of mineral metabolism (serum phosphorous, calcium, Ca x P, and iPTH) and the lipid profile (total, LDL, HDL, and non-HDL cholesterol, and triglycerides) in dialysis patients. After application of inclusion/exclusion criteria, 17 core studies were statistically analyzed to determine the sevelamer treatment effect on the study parameters as demonstrated by simple, n-weighted, and inverse variance-weighted mean changes. Analysis of inverse variance-weighted mean changes indicated that sevelamer treatment was associated with a 2.14 mg/dL drop in serum phosphorus (P <.001), no significant overall effect on calcium (0.09 mg/dL, P =.364), significant decline in Ca x P product (15.91 mg(2)/dL(2), P <.001), 35.99 pg/mL reduction in iPTH (P =.026), significant reduction in total cholesterol (30.58 mg/dL, P <.001), 31.38 mg/dL drop in LDL cholesterol (P <.001), significant increase in HDL cholesterol (4.09 mg/dL, P =.008), and a significant reduction in triglycerides (22.04 mg/dL, P x.001). This meta-analysis suggests that sevelamer offers a dual therapeutic benefit in dialysis patients-a population at high risk for cardiovascular disease-by improving phosphorus control and the lipid profile, without altering serum calcium.

Calcium↗

PubMed2003

Sevelamer hydrochloride, a phosphate binder, protects against deterioration of renal function in rats with progressive chronic renal insufficiency.

BACKGROUND: Dietary phosphate restriction prevents renal function deterioration in animal models. This study examined whether sevelamer hydrochloride (Renagel(R); 'sevelamer' hereafter), a non-calcaemic phosphate binder could slow deterioration of renal function in rats with progressive renal insufficiency. METHODS: Wistar Kyoto male rats were singly injected with normal rabbit serum or rabbit anti-rat glomerular basement membrane serum. Three days later, rats were fed a powder diet containing 0, 1 or 3% sevelamer for 58 days. Time course changes of serum levels of blood urea nitrogen (BUN), creatinine, calcium, phosphorus and parathyroid hormone (PTH) were measured throughout, and creatinine clearance (CCr), kidney calcium content and renal histology examined at the end of the study. RESULTS: Sevelamer partially inhibited elevation of BUN and serum creatinine, and completely inhibited increases in serum phosphorus, PTH and calcium xphosphorus product. Sevelamer significantly prevented the decrease in CCr and kidney calcium content elevation. Kidney calcium content and BUN and serum creatinine were strongly positively correlated, and kidney calcium content and CCr strongly negatively correlated. Kidney calcium content correlated well with serum phosphorus, serum calcium x phosphorus product and PTH, but not serum calcium. Sevelamer treatment partly prevented histological deterioration of both glomerular and tubulointerstitial lesions of the kidney. CONCLUSIONS: The results suggest that sevelamer protects against renal function deterioration by maintaining kidney calcium at a low level as a result of reducing serum phosphorus and PTH.

Animals↗

PubMed2002

Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease?

OBJECTIVES: We sought to determine clinical and laboratory correlates of calcification of the coronary arteries (CAs), aorta and mitral and aortic valves in adult subjects with end-stage renal disease (ESRD) receiving hemodialysis. BACKGROUND: Vascular calcification is known to be a risk factor for ischemic heart disease in non-uremic individuals. Patients with ESRD experience accelerated vascular calcification, due at least in part to dysregulation of mineral metabolism. Clinical correlates of the extent of calcification in ESRD have not been identified. Moreover, the clinical relevance of calcification as measured by electron-beam tomography (EBT) has not been determined in the ESRD population. METHODS: We conducted a cross-sectional analysis of 205 maintenance hemodialysis patients who received baseline EBT for evaluation of vascular and valvular calcification. We compared subjects with and without clinical evidence of atherosclerotic vascular disease and determined correlates of the extent of vascular and valvular calcification using multivariable linear regression and proportional odds logistic regression analyses. RESULTS: The median coronary artery calcium score was 595 (interquartile range, 76 to 1,600), values consistent with a high risk of obstructive coronary artery disease in the general population. The CA calcium scores were directly related to the prevalence of myocardial infarction (p < 0.0001) and angina (p < 0.0001), and the aortic calcium scores were directly related to the prevalence of claudication (p = 0.001) and aortic aneurysm (p = 0.02). The extent of coronary calcification was more pronounced with older age, male gender, white race, diabetes, longer dialysis vintage and higher serum concentrations of calcium and phosphorus. Total cholesterol (and high-density lipoprotein and low-density lipoprotein subfractions), triglycerides, hemoglobin and albumin were not significantly related to the extent of CA calcification. Only dialysis vintage was significantly associated with the prevalence of valvular calcification. CONCLUSIONS: Coronary artery calcification is common, severe and significantly associated with ischemic cardiovascular disease in adult ESRD patients. The dysregulation of mineral metabolism in ESRD may influence vascular calcification risk.

Adult↗

PubMed2002

Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.

BACKGROUND: Cardiovascular disease is frequent and severe in patients with end-stage renal disease. Disorders of mineral metabolism may contribute by promoting cardiovascular calcification. METHODS: We conducted a randomized clinical trial comparing sevelamer, a non-absorbed polymer, with calcium-based phosphate binders in 200 hemodialysis patients. Study outcomes included the targeted concentrations of serum phosphorus, calcium, and intact parathyroid hormone (PTH), and calcification of the coronary arteries and thoracic aorta using a calcification score derived from electron beam tomography. RESULTS: Sevelamer and calcium provided equivalent control of serum phosphorus (end-of-study values 5.1 +/- 1.2 and 5.1 +/- 1.4 mg/dL, respectively, P = 0.33). Serum calcium concentration was significantly higher in the calcium-treated group (P = 0.002), and hypercalcemia was more common (16% vs. 5% with sevelamer, P = 0.04). More subjects in the calcium group had end-of-study intact PTH below the target of 150 to 300 pg/mL (57% vs. 30%, P = 0.001). At study completion, the median absolute calcium score in the coronary arteries and aorta increased significantly in the calcium treated subjects but not in the sevelamer-treated subjects (coronary arteries 36.6 vs. 0, P = 0.03 and aorta 75.1 vs. 0, P = 0.01, respectively). The median percent change in coronary artery (25% vs. 6%, P = 0.02) and aortic (28% vs. 5%, P = 0.02) calcium score also was significantly greater with calcium than with sevelamer. CONCLUSIONS: Compared with calcium-based phosphate binders, sevelamer is less likely to cause hypercalcemia, low levels of PTH, and progressive coronary and aortic calcification in hemodialysis patients.

Adult↗

PubMed2002

The effects of sevelamer hydrochloride and calcium carbonate on kidney calcification in uremic rats.

The control of serum phosphorus (P) and calcium-phosphate (Ca x P) product is critical to the prevention of ectopic calcification in chronic renal failure (CRF). Whereas calcium (Ca) salts, the most commonly used phosphate binders, markedly increase serum Ca and positive Ca balance, the new calcium- and aluminum-free phosphate binder, sevelamer hydrochloride (RenaGel), reduces serum P without altering serum Ca in hemodialysis patients. Using an experimental model of CRF, these studies compare sevelamer and calcium carbonate (CaCO(3)) in the control of serum P, secondary hyperparathyroidism (SH), and ectopic calcifications. 5/6 nephrectomized rats underwent one of the following treatments for 3 mo: uremic + high-P diet (U-HP); UHP + 3% CaCO(3) (U-HP+C); UHP + 3% sevelamer (U-HP+S). Sevelamer treatment controlled serum P independent of increases in serum Ca, thus reducing serum Ca x P product and further deterioration of renal function, as indicated by the highest creatinine clearances. Sevelamer was as effective as CaCO(3) in the control of high-P-induced SH, as shown by similar serum PTH levels, parathyroid (PT) gland weight, and markers of PT hyperplasia. Also, both P binders elicited similar efficacy in reducing the myocardial and hepatic calcifications induced by uremia. However, sevelamer caused a dramatic reduction of renal Ca deposition (29.8 +/- 8.6 micro g/g wet tissue) compared with both U-HP (175.5 +/- 45.7 micro g/g wet tissue, P < 0.01) and the U-HP+C (58.9 +/- 13.7 micro g/g wet tissue, P < 0.04). Histochemical analyses using Von Kossa and Alizarin red S staining of kidney sections confirmed these findings. The high number of foci of calcification in the kidney of uremic controls (108 +/- 25) was reduced to 33.0 +/- 11.3 by CaCO(3) and decreased even further with sevelamer (16.4 +/- 8.9, P < 0.02 versus CaCO(3)). Importantly, the degree of tubulointerstitial fibrosis was also markedly lower in U-HP+S (5%) compared with either U-HP+C (30%) or U-HP (50%). It is concluded that in experimental CRF in rats, despite a similar control of serum P and SH, sevelamer is more effective than CaCO(3) in preventing renal Ca deposition and tubulointerstitial fibrosis, including better preservation of renal function. These findings cannot be extrapolated to human disease, and further studies in patients are necessary to determine the benefits of either P binder.

Animals↗

PubMed2002

Absorption of colesevelam hydrochloride in healthy volunteers.

OBJECTIVE: To assess whether colesevelam hydrochloride is absorbed in healthy volunteers. METHODS: A single-center, open-label, radiolabeled study was performed with 16 healthy volunteers. Subjects were administered non-radiolabeled colesevelam hydrochloride 1.9 g twice daily for 4 weeks, followed by a single dose of [14C]-colesevelam 2.4 g (480 pCi). These subjects continued to receive non-radioactive colesevelam 1.9 g twice daily for 4 days after administration of the radiolabeled dose. Blood, urine, and feces were collected immediately prior to administration of [14C]-colesevelam and at specified intervals after administration. The whole-blood equivalent concentration of colesevelam was calculated using data collected throughout the 96 hours following radiolabeled drug administration. The proportion of [14C]-colesevelam excreted through urine or feces was calculated based on the amount of radioactivity recovered up to 216 hours after the radiolabeled dose. RESULTS: The mean cumulative total recovery of [14C]-colesevelam in urine and feces was 0.05% and 74%, respectively. Excluding 2 subjects for whom cumulative recovery was <25%, the mean cumulative fecal recovery was 82%. The mean maximum whole-blood equivalent concentration of colesevelam was 0.165+/-0.10 microg equiv/g 72 hours after administration of [14C]-colesevelam, which was estimated to be 0.04% of the administered dose. All blood samples contained <4 times the number of background counts (dpm). CONCLUSIONS: The cumulative recovery data in urine and feces are consistent with the conclusion that colesevelam is not absorbed and is excreted entirely through the gastrointestinal system.

Allylamine↗

PubMed2002

Effect of colesevelam on lovastatin pharmacokinetics.

OBJECTIVE: To assess potential interactions of colesevelam hydrochloride and lovastatin in healthy volunteers when lovastatin alone was administered with dinner, both lovastatin and colesevelam were administered with dinner, and colesevelam was administered with dinner and lovastatin was administered 4 hours later with a snack. METHODS: A single-center, open-label, 3-period, crossover drug interaction study was performed with 22 healthy volunteers. Blood samples were collected at specified intervals before and after dosing, and plasma concentrations of lovastatin and lovastatin hydroxyacid were measured using a liquid chromatography/mass spectroscopy/mass spectroscopy method. RESULTS: Maximal concentration (Cmax), AUC from time 0 to the last time point measured (AUC0-t), and AUC0-infinity values for lovastatin were 102%, 94%, and 104%, and for lovastatin hydroxyacid were 102%, 91%, and 92%, respectively, of control values when colesevelam and lovastatin were coadministered with dinner. Administration of colesevelam with dinner and lovastatin 4 hours later with a snack resulted in a decreased Cmax and AUC0-t for lovastatin (63% and 37%, respectively; p < 0.05) and an increased Cmax and AUC0-t for lovastatin hydroxyacid (61% and 50%, respectively; p < 0.05), both compared with lovastatin alone administered with dinner. CONCLUSIONS: Colesevelam had no significant effect on lovastatin pharmacokinetics when coadministered with lovastatin at dinner. A split-dosing regimen resulted in alterations in pharmacokinetic parameters for lovastatin and lovastatin hydroxyacid that are likely due to known differences in the pharmacokinetics of lovastatin when administered to patients with meals or in a fasting state.

Adult↗

PubMed2002

Sevelamer, a phosphate-binding polymer, is a non-absorbed compound.

OBJECTIVE: To examine the absorption, distribution and excretion of sevelamer hydrochloride in rats and humans. PARTICIPANTS: Twelve male Sprague-Dawley rats were used in the animal study, and twenty human volunteers participated in the clinical trial. METHODS: In the animal study, six rats received a single oral dose of [(3)H]sevelamer and six rats were pretreated with unlabelled sevelamer in the diet for 28 days followed by a single dose of [(3)H]sevelamer on day 29. Total urine and faeces were collected at intervals up to 72 hours post dose, and tissues were obtained at the time of sacrifice. In the clinical trial, subjects received a single oral dose of [(14)C]sevelamer following 28 days of pretreatment with unlabelled sevelamer. Blood, urine and faeces samples were collected at intervals up to 96 hours. RESULTS: In the rat study, no significant urinary excretion of radioactivity was observed. The average recovery of radioactivity in the faeces was 98% in the single-dose group and greater than 100% in the group pretreated with unlabelled sevelamer for 28 days. A total of less than 0.1% of the dose was found in the tissues. In the human study, no detectable amount of (14)C was found in the blood of any subject at any time. The majority of subjects had no detectable amounts of (14)C recovered in the urine. In subjects where (14)C was recovered in the urine, less than 0.02% was detected, a level equivalent to the free (14)C detected in the [(14)C]sevelamer preparation. On average, greater than 99% of the administered dose was recovered in the faeces of the subjects. CONCLUSION: These studies demonstrate that sevelamer is a non-absorbed compound.

Absorption↗