Do Animals Throw Up After Taking Phosphorus Binders

Ther Clin Run a risk Manag. 2008 Oct; 4(five): 887–893.

Phosphate binding therapy in dialysis patients: focus on lanthanum carbonate

Abstract

Hyperphosphatemia is an inevitable outcome of end stage chronic kidney disease and is nowadays in the bulk of dialysis patients. Contempo observational information has associated hyperphosphatemia with increased cardiovascular mortality among dialysis patients. Dietary restriction of phosphate and current dialysis prescription practices are non enough to maintain serum phosphate levels within the recommended range so that the majority of dialysis patients require oral phosphate binders. Unfortunately, conventional phosphate binders are not reliably effective and are associated with a range of limitations and side effects. Aluminium-containing agents are highly efficient but no longer widely used because of well established and proven toxicity. Calcium based salts are inexpensive, effective and near widely used but there is now business organisation about their clan with hypercalcemia and vascular calcification. Sevelamer hydrochloride is associated with fewer adverse effects, but a big pill burden and high cost are limiting factors to its wider use. In addition, the efficacy of sevelamer as a monotherapy in lowering phosphate to target levels in severe hyperphosphatemia remains debatable. Lanthanum carbonate is a promising new non-aluminium, calcium-complimentary phosphate binder. Preclinical and clinical studies have demonstrated a good safety profile, and information technology appears well tolerated and effective in reducing phosphate levels in dialysis patients. Its identified adverse events are plain mild to moderate in severity and mostly GI related. It appears to be effective as a monotherapy, with a reduced pill brunt, but like sevelamer, it is significantly more expensive than calcium-based binders. Data on its safety contour over 6 years of treatment are now available.

Keywords: hyperphosphatemia, lanthanum carbonate, dialysis, phosphate binding

Introduction

Hyperphosphatemia is an well-nigh inevitable consequence of chronic kidney disease (CKD). Information technology occurs in the majority of dialysis patients and continues to stand for a major claiming to clinical nephrologists. Indeed more than than 36% of United kingdom of great britain and northern ireland haemodialysis patients take plasma phosphate of ≥one.8 mmol/L (five.five mg/dL) despite dietary manipulation and prescription of oral phosphate binders (Lamb et al 2007).

Normal kidneys filter big amounts of organic phosphate of which more than ninety% is reabsorbed by the renal tubules. Early renal dysfunction reduces filtered phosphate but likewise decreases tubular reabsorption, then that the urinary phosphate excretion continues to match gastrointestinal (GI) absorption. Consequently, the net rest between phosphate input and output is maintained for a period of time with only fiddling change in serum phosphate levels. All the same, as renal function deteriorates farther, this homeostatic machinery fails resulting in positive phosphate rest and progressive hyperphosphatemia.

Untreated hyperphosphatemia tin lead to secondary hyperparathyroidism (SHPT), renal osteodystrophy, vascular calcification and increased morbidity and mortality (Lowrie and New 1990; Delmez and Slatopolsky 1992; Block et al 2004). Retrospective cross-sectional studies advise that a serum phosphate greater than 6.5 mg/dL (2.10 mmol/L) is associated with a 27% college mortality risk (relative adventure [RR] +1.27) compared with patients with a phosphate level of 2.4–half dozen.5 mg/dL (0.78–two.10 mmol/L), and relative risk increases as serum phosphate rises (Cake and Port 2000). Block et al found that a calcium × phosphate product in a higher place 72 mg²/dLⁱⁱ was as well associated with a significantly higher relative risk of death (RR + 1.34), but this is non surprising if the majority of the take chances is attributed to the phosphate. Consequently, phosphate control remains an important therapeutic target in management of CKD, not only to halt progression to secondary hyperparathyroidism but also to reduce the chance of vascular calcification and cardiovascular mortality, although no prospective interventional studies currently exist to demonstrate that this is achievable.

Unfortunately phosphate control has not been significantly improved over the past two decades. Several factors may accept contributed to this, including the difficulty of adhering to renal diets, phosphate binder prescriptions and inadequate phosphate clearance by dialysis. In addition, factors such as cost, tolerability, palatability, safety, and efficacy are too important (Tabular array 1).

Table ane

Suggested characteristics of an ideal oral phosphate binder

Loftier analogousness for binding phosphate – low dose (pill burden) required

Rapid phosphate binding regardless of ambient pH

Low solubility

Low systemic absorption (preferably none)

Non toxic and without side furnishings

Solid oral dose form

Palatable – encourages compliance

Inexpensive

Nosotros review current management of hyperphosphatemia with a item focus on the pharmacology, clinical efficacy, and safety contour of lanthanum for treatment of elevated serum phosphate in dialysis patients.

Management of hyperphosphatemia in chronic kidney disease

The standard arroyo to direction of elevated serum phosphate in CKD includes dietary restriction, dialysis and drug treatment using oral phosphate binders. Unfortunately, at that place are many limitations to this approach which may explain the current inability to adequately treat hyperphosphatemia.

Firstly, dietary phosphate brake is impractical for many patients who mostly eat pre-prepared, supermarket meals rather than freshly prepared foods as in the relatively recent past. In addition it can only be restricted to a sure extent without risking protein malnutrition, particularly in elderly patients (Kopple and Coburn 1973).

Secondly, conventional thrice-weekly, 4-hour hemo-dialysis removes approximately 1000 mg of phosphate each treatment, but this is generally insufficient to maintain phosphate levels within the recommended targets even if oral phosphate intake is significantly restricted. Peritoneal dialysis is niggling better in this respect (Delmez et al 1982). Kinetic studies of hemodialysis take shown that since phosphate is predominantly intracellular, serum levels drop apace in the first 1–2 hours of dialysis and then reach a plateau. They then rising relatively quickly in the commencement few hours after termination of dialysis, the so-called 'rebound phenomenon'. Although short daily and deadening nocturnal haemodialysis may be effective in reducing serum phosphate levels, logistic, toll and patient credence bug limit widespread usage of such modalities (Lowrie and Lew 1990). Thus around 90% of dialysis patients continue to demand boosted therapeutic maneuvres to improve their phosphate levels.

Traditionally available oral phosphate binding agents, though effective in lowering serum phosphate levels are not platonic and nearly have limitations of ane sort or another (Table 2). Aluminium-based phosphate binders are highly efficient only have been associated with cognitive disturbances, osteomalacia, and anemia which restrict utilize (Wills and Savory 1983; Gonzalez-Revalderia et al 2000). No safe dose of aluminium has been identified and dialysis patients who take information technology even in modest doses have been reported to develop clinical evidence of toxicity (Malluche 2002). Nonetheless aluminium salts are still used equally curt term 'salvage' therapy to reach acute control of high phosphate levels, and are too used in patients whose prognosis is felt to be so short, because of other co-morbidities, that the advantages may outweigh the risks.

Table 2

Comparing of currently available oral phosphate binders

Phosphate binder	Advantages	Disadvantages
Calcium carbonate	Aluminium free	Efficacy influenced past pH
	Moderately effective	Unpalatable
	Moderate pill burden	Hypercalcemia
	Cheap	GI side effects
		Possible ectopic calcification
Calcium acetate	Aluminium free	Large tablets need to be swallowed
	Efficacy some what pH dependent	Hypercalcemia
	Moderately cheap	GI side effects
	Lower calcium load than carbonate	Possible ectopic calcification
	Calcium free
Aluminium salts	Loftier efficacy regardless of pH	Aluminium toxicity
	Cheap	No definite safe dose
	Not pH dependent	Frequent monitoring needed
Magnesium salts	Moderate pill burden	GI side effects
	Calcium and aluminium free	Not widely used
	Moderate efficacy	Magnesium monitoring
	Moderate pill brunt
Sevelamer	Calcium and aluminium gratis	Expensive
	No GI tract absorption	Efficacy influenced by pH
	Moderate efficacy	High pill burden
	Reduces total and LDL cholesterol	GI side effects
		Binds fat-soluble vitamins
Lanthanum carbonate	Calcium and aluminium free	Expensive
	Chewed, non swallowed whole	GI side furnishings
	High efficacy regardless of pH	Minimal GI assimilation
	Depression pill burden

Calcium-based binders (acetate and carbonate) are effective and cheap simply their prolonged administration can result in hypercalcemia in over 50% of patients, especially when administered with vitamin D analogues (Schaefer et al 1992). In add-on they tin can result in over-suppression of parathyroid hormone (PTH), adynamic os, and are associated with both soft tissue and vascular calcification (Goodman et al 2000; Goodman 2001). Nevertheless, information technology is worth remembering that vascular calcification was first seen in the 1980s when aluminium hydroxide was the just commonly available phosphate binder. Several investigators have found calcium acetate to be more than constructive in bounden abdominal phosphate, per mmol of administered elemental calcium, than calcium carbonate (Mai et al 1989). Still, compliance and patient tolerability are mostly poor with calcium acetate and the studies showing a greater reduction in mean serum phosphate level, compared with the aforementioned dose of calcium carbonate, were relatively curt-term (Qunibi et al 2004).

Magnesium-containing phosphate binders can exist used as an alternative to calcium-based agents merely generally they are less effective, and are associated with increased serum magnesium levels and diarrhea. Notwithstanding, magnesium iron hydroxycarbonate is a new oral phosphate binder currently undergoing clinical trials, with promising results presented in abstruse grade just and then far (McIntyre 2007).

Sevelamer hydrochloride was the starting time synthetic not-aluminium and calcium-complimentary phosphate binder to become available. It was originally adult to lower plasma lipids and has this beneficial side issue in CKD patients. In several open up label studies sevelamer appears as effective as calcium-based binders in lowering phosphate, but without the tendency to promote hypercalcemia (Bleyer et al 1999). Furthermore, there is some evidence that sevelamer hydrochloride can benumb coronary and aortic calcification compared with calcium-based phosphate binders (Chertow et al 2002). Despite these advantages, GI disturbances, metabolic acidosis, and cost are limiting factors affecting the wider use of sevelamer hydrochloride. Unfortunately the large pill burden required to attain target phosphate levels can adversely affect patient adherence. Yet, sevelamer remains an important current therapy in the management of hyperphosphatemia. More than recently lanthanum carbonate became widely available in the US (Jan 2005) and European union (July 2006), and is also a nonaluminium-, noncalcium-based folder.

Pharmacology

Lanthanum is a naturally occurring rare-earth element with a molecular weight of 139 Da and diminutive number 57. The element was discovered by Carl Gustaf Mosander in 1839. It is particularly arable in China where information technology is mined, just tin can exist found in many dark-green leafy vegetables and also in tap water in the UK. As a phosphate folder, lanthanum is ingested as the carbonate salt, and information technology dissociates in the upper GI tract to the lanthanum ion (Laⁱⁱⁱ⁺). It binds phosphate ionically, optimally at pH 3–5, while retaining its phosphate-binding capacity across the full pH range from 1 to vii (Hutchison and Al-Baaj 2005). Unlike calcium-based binders and sevelamer hydrochloride, lanthanum has been shown in vitro to bind phosphate efficiently even at the low pH institute in the tummy, every bit well as the high pH values institute in the duodenum and jejunum. This range of pH for binding phosphate is similar to that seen with aluminium salts (3–v).

Beast studies have shown that lanthanum has similar phosphate binding efficacy to aluminium, only dramatically lower oral bioavailability. In a nephrectomized rat model it reduced urinary phosphate levels to the aforementioned extent as aluminium, and more than effectively than calcium carbonate or sevelamer (Finn et al 2004). Lanthanum has a depression potential for accumulation with only 0.00005% of the oral dose existence captivated via the canine GI tract (Shire Pharmaceuticals Group, data on file) compared with 0.05%–0.1% for aluminium (Knoll et al 1984). The small-scale absorbed fraction is eliminated primarily by the liver, not the kidneys, with 85% of this being eliminated in bile and 13% directly beyond the gut wall (Hutchison 2004; Damment and Pennick 2007). In rats 99.iii% of an oral dose is excreted in faeces with only 0.004% excreted in urine (Hutchison 2004). In homo the accented bioavailability of lanthanum (administered as lanthanum carbonate) was extremely depression (0.00127% ± 0.00080%), with private values in the range of 0.00015%–0.00224% (Pennick et al 2006). Renal clearance was negligible after oral administration (1.36 ± 1.43 mL/min), and intravenous assistants confirmed this low renal clearance (0.95 ± 0.60 mL/min) – just i.7% of full plasma clearance. Furthermore, in contrast to aluminium, lanthanum does not cross the blood brain bulwark, then that the potential for neurological adverse side effects is extremely low (Damment et al 2007). Lanthanum carbonate is not known to induce whatever systemic drug reactions and has no effect on cytochrome P450 enzymes.

Clinical efficacy

The results of published data on lanthanum carbonate demonstrate that lanthanum has many of the characteristics of an effective phosphate binder. Pre-clinical creature studies suggested that lanthanum may be similar to aluminium in phosphate lowering capacity just with a much more favourable safety contour.

Phase II studies revealed a statistically significant decrease in phosphate levels in patients receiving lanthanum carbonate at a dose of 1500–3000 mg/twenty-four hours in ii double bullheaded placebo controlled studies (Hutchison et al 2004; Al-Baaj et al 2005). The maximal subtract in serum phosphate levels occurred subsequently 3 weeks of treatment and was maintained over the iii–half-dozen weeks of treatment.

Three large multicenter phase III studies were performed to evaluate the efficacy and safety of lanthanum carbonate. The start trial was a 13-week randomized, double-bullheaded, placebo-controlled, parallel-group study which showed a highly significant difference in the mean serum phosphate levels between lanthanum and placebo groups (Joy and Finn 2003). Serum phosphate levels were controlled at <one.ix mmol/L in 59% of patients receiving lanthanum vs 23% in the placebo group. Moreover, 66% of the lanthanum-treated group maintained a controlled phosphate level at report cease signal, compared with 31% of the placebo group. Ca × P product (52.37 ± xiv.89 vs 66.59 ± 18.30 mg/dL; p < 0.0001), and serum PTH levels (209.41 ± 152.65 vs 291.80 = 194.82 pg/mL; p < 0.01) were significantly lower with lanthanum carbonate treatment than with placebo.

In a 2nd large prospective, randomized, European, multi-center, open label comparator trial, the efficacy of lanthanum carbonate was compared with calcium carbonate (Hutchison et al 2005). In full around 800 patients were randomized (533 to lanthanum and 267 to calcium carbonate). After 1–3 weeks of 'washout' from any previous folder therapy, patients with hyperphosphatemia (serum phosphate >ane.viii mmol/L (5.58 mg/dL)) were randomized to 5 weeks of dose titration with either lanthanum carbonate (375–3000 mg/day) or calcium carbonate (1500–9000 mg/ day) followed by a 20-week maintenance period. The master end indicate was reduction of serum phosphate levels to ≤1.8 mmol/L. The secondary efficacy parameter was maintenance of phosphate control at <i.8 mmol/L for 6 months or longer. PTH, calcium, and calcium × phosphate product levels were also monitored throughout the study.

Later on 9 weeks of handling both groups had serum phosphate levels of around 1.69 mmol/L (Figure 1). The proportion of patients achieving controlled phosphate levels of <1.eight mmol/Fifty was similar in both treated groups (lanthanum 65.8%, calcium 63.9%) at the end of maintenance phase (p = NS). The reduction in calcium × phosphate production was more often than not greater in the lanthanum carbonate group at the end of the maintenance phase −1.59 vs −1.ii mmol/L). Perhaps near importantly from a clinical perspective, there was a significantly higher incidence of hypercalcemia in the calcium-treated group (twenty.2%) than in the lanthanum group (0.four%), as ane would look with a noncalcium-based binder.

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Mean serum phosphate levels during titration and maintenance handling in the ITT population.

A similar just longer-term study was performed in the US, in which lanthanum monotherapy was compared with any other standard phosphate binder or combination of binders (Finn 2006). Later washout, patients were randomized to receive lanthanum carbonate (n = 682) or their pre-study phosphate folder (northward = 677). Over a 6-week menstruum, lanthanum carbonate was titrated to a maximum daily dose of 3000 mg elemental lanthanum (serum phosphate target levels for titration were ≤1.xc mmol/L). Over 2 years of follow up, phosphate command was similar in both groups but in the lanthanum group serum calcium was lower and serum PTH levels were maintained in the range recommended by Yard/DOQI. The well-nigh common agin events were gastrointestinal. The incidences of events in the lanthanum and standard therapy groups were nausea, 37% vs 29%; vomiting, 27% vs 22%, and diarrhea (24% in each group). At that place was no indication of liver toxicity, suppression of erythropoiesis, or changes in the mini-mental state test, and the authors concluded that the 2-year tolerability and efficacy of lanthanum were similar to those seen with any other standard therapy.

Subsequently the effect of lanthanum carbonate compared with calcium carbonate on development of renal osteodystrophy was evaluated in an open up label bone biopsy study among patients undergoing dialysis (D'Haese et al 2003). At base line 98% of patients in each group had evidence of renal osteodystrophy in their bone biopsy. Ninety-eight patients were randomized to receive lanthanum or calcium carbonate at a dose of 3750 or 9000 mg/day respectively for 1 year, followed past a repeat bone biopsy. After 1 year of treatment, 63 paired bone biopsy samples were analyzable. A greater proportion of patients with low bone turnover lesions (adynamic os or osteomalacia) at their baseline biopsy approached normalization on lanthanum treatment, compared to those given calcium (71% vs 43% respectively). At the finish of the written report thirty% (north = 9) of calcium-treated patients had adynamic os histology, compared with only 9% (n = 3) of the lanthanum-treated grouping. Moreover, no evidence of any agin outcome on osteoblast function could be seen, and there was no correlation betwixt bone lanthanum content and parathyroid hormone levels.

Safety data

Preclinical brute studies of lanthanum have shown no adverse effects at doses upwards to 2000 mg/kg torso weight, suggesting a large safe margin for this compound. More than chiefly clinical studies take shown no bear witness of toxicity affecting liver, bone or brain.

In common with all oral phosphate binders, lanthanum carbonate causes some GI side furnishings in around 20% of patients, but these seem to be relatively minor in well-nigh (intestinal hurting, nausea, vomiting, diarrhea, and constipation). Avoidance of hypercalcemia is the major benefit of any noncalcium-based binder, and this may prove to be lanthanum's biggest safety benefit.

Long-term safety of lanthanum has been examined in a number of open-label extension studies with exposure over vi months (Hutchison et al 2005), 2 years (Finn 2006), 3 years (Hutchison et al 2006), and most recently vi years (Hutchison et al 2008). In all these studies no testify of toxicity has been seen, and in particular no adverse effects related to liver, bone, or brain, which take been frequently raised every bit possible target organs despite the paucity of supporting data.

In the large phase III prospective study of 197 patients randomized to receive either lanthanum carbonate or any other 'standard' phosphate binders, bone biopsies were obtained at baseline and again later either one or 2 years of treatment. No agin furnishings on bone histology were seen in the lanthanum group. In another study 11 patients selected at random who had been in an open-characterization extension report and taking lanthanum carbonate for more than than four years showed no testify of depression turnover or aluminium-like effects in their bone biopsies. Clinical studies with upward to half-dozen years follow up have demonstrated no hepatotoxic effects related to handling in terms of liver enzyme changes.

The place of lanthanum in treatment of hyperphosphatemia

On the basis of its proven efficacy and safety profiles, information technology is justifiable to consider lanthanum carbonate as a first-line phosphate binder for dialysis patients. Yet, such decisions are rarely made on solely clinical grounds, and while it is clearly effective without evidence of toxicity, it is also expensive, with three 500 mg lanthanum tablets costing approximately the aforementioned as five 800 mg sevelamer pills. However, once the sevelamer prescription increases beyond this number of pills, the dose of lanthanum becomes cheaper at Britain prices. Furthermore the dose of lanthanum tin exist increased without increasing the number of tablets, since it is manufactured in unlike strengths – 500, 750, and 1000 mg – making it unique amid phosphate binders.

Lanthanum carbonate and sevelamer are both significantly more than expensive than calcium-based binders. In the light of electric current financial constraints and the rising cost of medical care, a cost/benefit pharmaco-economical study comparing lanthanum carbonate with other phosphate binders is warranted merely is virtually impossible without conducting prospective outcome studies.

The reduced pill burden combined with palatability and tolerability may lead to improvement in patient adherence to therapy, and therefore amend phosphate control, although adherence is non solely related to pill burden. Phosphate can be controlled in most patients with a dose between 1500 and 3000 mg daily, so that the prospect of 2–3 tablets daily is existent.

In a multicenter, open-label trial, patients on a stable dialysis regimen were screened while receiving phosphate-binder therapy, so entered into a washout phase (Hutchison and Laville 2008). Patients with serum phosphate >1.78 mmol/L later washout entered into the primary 12-week handling phase (N = 367), during which they were treated to target (K/DOQI: 1.13–1.78 mmol/L) with lanthanum carbonate monotherapy. Mean serum phosphate levels were significantly reduced afterwards 12 weeks of lanthanum carbonate monotherapy vs previous phosphate-folder therapy. The mean number of phosphate-folder tablets existence taken per 24-hour interval at screening was 7.six, but during treatment with lanthanum carbonate, most patients were taking doses of upward to 3000 mg/24-hour interval, achievable with 3 × 1000 mg tablets per day. These findings propose that lanthanum carbonate monotherapy offers effective control of serum phosphate and, owing to a low tablet burden, may assistance to simplify the management of hyperphosphatemia in patients with CKD Stage 5.

Conclusion

Hyperphosphatemia is prevalent in the dialysis population and is considered by many to exist an independent take chances cistron associated with cardiovascular morbidity and bloodshed. Its command remains a challenging issue for clinical nephrologists because none of the traditional therapeutic approaches announced entirely satisfactory. Dietary restrictions are difficult to follow and standard hemodialysis is inadequate for removal of phosphate, then that the vast majority of dialysis patients require oral phosphate binders. Until recently none of the available agents fulfilled the criteria of an ideal phosphate binder. The introduction of sevelamer hydrochloride and subsequently lanthanum carbonate represents a meaning development in phosphate direction. Both are nonalu-minium, calcium-free agents. Sevelamer achieves constructive phosphate lowering and may attenuate progression of vascular calcification in hamodialysis patients. However, its large pill burden and loftier price are major disadvantages which take adversely affected treatment compliance and the wider use of sevelamer.

Lanthanum carbonate represents another step on the way to consummate phosphate control. Evidence suggests that information technology is an effective, well tolerated and safe phosphate binder. Lanthanum does non crusade hypercalcemia, is effective in reducing calcium × phosphate product, and may have a positive effect on bone histology.

Footnotes

Disclosures

AJH has received research grants from Shire Pharmaceuticals and has a paid consultancy position with Shire. IAM has no conflicts to disembalm.

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