Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

43rd Congress of the European Renal Association/European Dialysis and Transplant Association

Glasgow, United Kingdom / July 15-18, 2006

As speakers here emphasized, mortality rates in hemodialysis patients often exceed those from cancer, at reported rates in excess of 20% a year. Excess mortality in this vulnerable population is largely driven by cardiovascular (CV) events and it has been speculated that certain disorders of mineral metabolism—elevations in serum phosphorus and calcium in particular—may contribute to excessive CV disease risk. As reported by Block et al. (J Am Soc Nephrol 2004;15:2208-18), for example, serum phosphorus concentrations in excess of 1.61 mmol/L were associated with an increased relative risk of death in a large, nationally representative database of hemodialysis patients, with mortality risk essentially doubling once serum phosphorus levels reached ³2.91 mmol/L.

In the same study, higher serum calcium concentrations were also associated with an increased risk of death, as was moderate to severe hyperparathyroidism. As indicated by Dr. John Cunningham, Professor of Nephrology, Royal Free and University College Medical School, London, UK, “Thus, if we take patients with the highest phosphate levels and control their phosphorus better, we may reduce mortality risk.”

He added that so far, however, efforts to reach target serum phosphorus levels set by the Kidney Disease Outcomes Quality Initiative (K/DOQI) are “disappointing,” with nearly 50% of patients remaining above K/DOQI recommended targets, according to a study by Young et al. (Kidney Int 2005;67:1179-87).

Part of the reason why target levels are not reached is likely related to current treatment options, “which are not particularly good,” as Dr. Cunningham noted. Regimens may also be implemented “suboptimally,” he observed, with patients struggling to take multiple tablets of phosphate binders with each meal on top of other medications needed to control comorbid disorders. Thus, reducing the pill burden when managing hyperphosphatemia in the dialysis patient has the potential to improve adherence, speakers here agreed.

As presented by Dr. Nirupama Vemuri, South Florida Nephrology Group, Coral Springs, Florida, the non-calcium-based phosphate binder lanthanum carbonate provides comparable control of serum phosphorus as other phosphate binders but it does so with fewer tablets. In a poster presentation of her study, over 2700 chronic kidney disease patients were switched from a variety of other phosphate binders at study entry to an initial dose of lanthanum carbonate of 1500 mg/day, divided with meals. The dose was adjusted weekly to a maximum daily dose of 3750 mg/day. (It should be noted that in this study, patients took the original formulations of 250 and 500 mg and not the newer, higher-dose formulations of 750 and 1000 mg). As Dr. Vemuri and colleagues reported, both at week 12 and 16, serum phosphorus levels were maintained at or near levels recorded with previous phosphate-binder therapies, and the proportion of patients with controlled serum phosphorus (<1.77 mmol/L) remained constant at 42% in both the pre- and post-study analysis.

According to Dr. Vemuri, at week 12, there was also a significant reduction in the mean average daily tablet burden, as well as in total daily dose, compared with previous phosphate-binder therapy. For patients on previous calcium-based phosphate binders, the number of tablets required at baseline to achieve phosphorus control was 8.3, at a total daily dose of 5.39 g of calcium/day. A mean of 9.6 tablets were required by patients taking sevelamer at baseline, at a mean daily dose of 7.6 g. For those taking a combination of calcium-containing and non-calcium-containing phosphate binders, the mean tablet burden at baseline was 14.9.

Sixteen weeks after patients were switched to lanthanum carbonate, the mean tablet burden was reduced to 5.8 pills/day and 5.9 pills/day in the calcium and sevelamer binder groups, respectively, and to 6.5 tablets/day in the combination group, which translated into approximately a 30 to 40% reduction in overall pill burden for the monotherapy groups and up to a 56% reduction in tablet burden in the combination group. “At the end of the 12-week titration period, 73% of patients reported that overall, they preferred lanthanum carbonate over their previous phosphate binders,” the authors observed, a response echoed by 83% of physicians.

Dr. Vemuri stated, “Hyperphosphatemia causes CV morbidity and mortality and compliance plays a major role in getting high phosphate levels down.” She added that the new higher-dose formulations “will further decrease the tablet burden by 60 to 80% compared with both the lower- dose formulations of lanthanum carbonate as well as other phosphate binders.”

Other Study Findings

In a separate open-label study presented by Dr. Rajnish Mehrotra, Assistant Professor of Medicine, David Geffen School of Medicine, University of California at Los Angeles, he and co-investigators tested all optimized formulations given as 250, 500, 750 and 1000 mg chewable tablets.

A total of 509 patients—approximately half of whom were on sevelamer prior to being switched to lanthanum carbonate and 40% of whom were on a calcium-containing phosphate binder—received lanthanum carbonate titrated from 1500 mg/day to either 2250 or 3000 mg/day in order to reach serum phosphorus targets of 3.5 to 5.5 mg/dL (1.13 to 1.78 mmol/L). A second phase of this open-label study then had patients continue on doses of up to 3000 mg/day or receive a forced dose titration of up to 4500 mg/day.

Patient and physician satisfaction questionnaires were collected at baseline and at treatment weeks 4, 8 and 24, indicated the investigators. At week 24, 78% of patients and 88% of physicians reported a significantly higher level of overall satisfaction (P<0.001) with the new formulations compared with 63% of patients and 66% of physicians for previous phosphate-binder therapy. Approximately 60% of patients also indicated they preferred the higher dose formulation because of ease of use, decreased pill burden and increased ability to adhere to the phosphate-binding regimen.

“I think, hopefully, that the new formulations of lanthanum carbonate will improve adherence to therapy because if you can reduce the number of pills a patient has to take, they will hopefully take their pills more regularly and thus achieve better phosphorus control,” Dr. Mehrotra noted, adding that while not yet confirmed, improved phosphorus control may likely improve outcomes for patients.

Gaining rapid control of elevated serum phosphorus levels with a higher initial dose may also foster patient confidence that treatment is indeed effective. As indicated by Dr. George Porter, Professor Emeritus of Medicine, Oregon Health Sciences University, Portland, if physicians must constantly increase the number of pills patients need to take, “they get discouraged.”

Thus, investigators sought to establish the exact dose of lanthanum carbonate that would reduce serum phosphorus levels most rapidly. For the study, serum phosphorus control was defined as £1.77 mmol/L, as recommended by K/DOQI guidelines. Two studies were retrospectively analyzed: one in which patients were randomized to receive lanthanum carbonate at 225, 675, 1350 and 2250 mg/day (in divided doses with meals), and a second study in which the dose was titrated over a course of five weeks from 375 mg/day to a maximum of 3000 mg/day using 125-mg or 250-mg tablets.

Analysis of the first study indicated that an initial dose of 2250 mg led to the most rapid serum phosphorus control at a median time of seven days. In the second study, investigators noted a “direct association” between baseline serum phosphorus values and the dose required to control phosphorus, with higher baseline levels requiring higher doses to achieve control. Fifty-eight per cent of patients with baseline serum phosphorus levels 1.77 to 2.42 mmol/L achieved phosphorus control at study end, as did 53% of those with baseline serum levels of >2.42 to 2.91 mmol/L and 52% of those with baseline serum phosphorus levels of >2.91 mmol/L.

Importantly, both studies indicated that the incidence of adverse events did not increase with the higher doses. “Overall, we found that between 2250 and 3000 mg/day of lanthanum carbonate produces very rapid phosphorus control,” confirmed Dr. Porter. However, he emphasized that it is critical patients understand they need to take their pills during or following meals, in order for the medication to be most effective.

K/DOQI Guidelines

The most recent K/DOQI guidelines now recommend lower target serum phosphate levels than previous guidelines, with optimal control now set at between 1.13 and 1.78 mmol/L. In another phase III study, investigators assessed the efficacy of lanthanum carbonate to control serum phosphate levels to the most recent K/DOQI targets in patients receiving either single or combination phosphate-binder therapy.

As presented by lead author Dr. Alastair Hutchison, Renal Unit, Manchester Royal Infirmary, and Honorary Lecturer in Medicine, University of Manchester, UK, 274 patients received lanthanum carbonate 1500 mg/day, given in three divided doses with meals, for an interval of 12 weeks. This dose could be increased by 750 mg/day each week to a maximum daily dose of 4500 mg/day in order to achieve the recommended K/DOQI targets. Tablets available contained doses of 250, 500, 750 and 1000 mg. Prior to being switched, 57% were on a single phosphate binder while 41% were taking two or more binders. The mean serum phosphate level at screening among patients receiving a single binder was 1.99 mmol/L, and only 36% of patients in the monotherapy group met K/DOQI targets for serum phosphorus.

After 12 weeks of lanthanum carbonate, mean serum phosphate levels were 1.83 mmol/L and 52% of patients had met K/DOQI targets. Among patients receiving two or more binders at baseline, mean phosphate levels at screening were similar at 1.97 mmol/L and 35% of patients had achieved K/DOQI targets. Twelve weeks later, serum phosphorus levels had dropped to 1.87 mmol/L and 43% of patients previously receiving two or more binders had now achieved K/DOQI target levels.

As investigators indicated, the average dose required by patients in this study was approximately 3000 mg/day. Thus, the majority of patients requiring treatment for hyperphosphatemia could be controlled with a single, 1000-mg chewable tablet taken with each meal, investigators observed. Most adverse events were gastrointestinal in nature and included mild to moderate vomiting, nausea and diarrhea.

“If you have patients who are taking a large number of phosphate binder tablets, you can improve phosphate control in a significant number of patients by switching to lanthanum carbonate and you can do that with a significantly reduced number of tablets as well,” concluded Dr. Hutchison.

Findings After Six Years

In several presentations, investigators examined the safety profile of lanthanum carbonate, now used for up to six years in some patients. In a two-year extension study carried out in a subgroup of patients who had taken part in four previous studies, investigators sought evidence of serious adverse events or new ones that might have emerged after up to six years of use. “Not all patients could complete the full six years,” Dr. Hutchison observed. Indeed, out of a cohort of 93 patients enrolled in this extension study, only 17 were able to complete the full six years of therapy. However, 26 patients completed five years of therapy, while 38 patients received four years of treatment.

This extension study showed that four patients (4.3%) developed a fracture, a rate that is very similar to that reported for other phosphate binders. Investigators noted that most patients experienced some sort of adverse event over the course of the extension trial, but only two reports of headache were felt to be treatment-related.

Importantly, no patient had two consecutive alanine aminotransferase or aspartate aminotransferase readings greater than three times the upper limit of normal, while plasma levels of lanthanum carbonate remained within the nanomolar range across the six years as well. “There is no other phosphate binder that has ever reported anything like this length of follow-up,” Dr. Hutchison told the audience, “and we saw no increase in frequency of adverse events over time, nor any evidence of new or unexpected adverse events with increasing exposure, either.”

Other investigators corroborated the lack of toxicity in both the liver and the brain. Prof. Marc De Broe, Professor of Medicine, Department of Nephrology and Hypertension, University Hospital Antwerp, Belgium, clearly demonstrated that after ingestion, lanthanum carbonate is minimally absorbed from the gastrointestinal tract and the small fraction of the agent that is absorbed is almost entirely bound by protein. Thus, levels that accumulate in bone are extremely low, even with long-term exposure. It is also almost entirely excreted by the biliary system and it merely passes through the liver, Prof. De Broe emphasized, being initially bound to transferrin, taken up by the lysosomes and subsequently eliminated via the bile canaliculus.

However, he did caution that patients with full-blown cirrhosis should not receive it. “If the lysosomal pathway is disturbed and if you disturb the elimination mechanism of that agent, it will accumulate in the serum and blood concentrations will go up, and then you can’t predict what the effect will be.”

Two animal experiments carried out by Prof. Stephen Damment, Hampshire, UK, confirmed researchers’ hypotheses that previous reports of lanthanum carbonate accumulating in the brain were the result of contamination from the compound being given in high concentration powder form in the diet and subsequently transferred from the skin of the animal to the brain during autopsy, and not from any ability of the compound to penetrate the blood-brain barrier.

Summary

Reducing and controlling phosphorus levels in chronic kidney disease patients becomes an even more important goal to achieve, particularly in light of the new lower levels indicated in the updated K/DOQI guidelines. Treating physicians must also continue reminding their patients that they need to take their pills during meals to ensure best results. Reducing pill burden with the optimized formulation of lanthanum carbonate will further encourage patients towards better compliance. Moreover, the formulation exhibits a satisfactory safety profile, without any apparent increase in the incidence of adverse events.

Note: At the time of printing, lanthanum carbonate is not available in Canada.