Lanthanum Carbonate Improves Serum P Control in Most CKD Stage 5 Patients

Marlene Busko

December 14, 2006

December 14, 2006 (San Diego) — Three phase 3 studies in patients with stage 5 chronic kidney disease (CKD) demonstrated different safety and efficacy aspects of the non–calcium-phosphate binder lanthanum carbonate (Fosrenol, Shire US Inc). Study results show that it is linked with slightly improved bone formation, provides effective serum phosphorus control for most patients when given as monotherapy, and seems safe in doses to 4500 mg/day in patients who do not respond to 3000 mg/day. These results were presented here at the American Society of Nephrology (ASN) Renal Week 2006.

According to a Shire press release, despite the availability of phosphate binders, fewer than 30% of dialysis patients are able to maintain serum phosphorus levels in the target range recommended by the Kidney Disease Outcome Quality Initiative (KDOQI) clinical practice guidelines: 3.5 to 5.5 mg/dL.

Richard A. Sherman, MD, from the Robert Wood Johnson Medical School, in New Brunswick, New Jersey, who was not involved with these studies, explained to Medscape that epidemiologic evidence shows there is a 17% lower mortality when serum phosphorus is 5.5 mg/dL vs 6.5 mg/dL. He added that if therapeutic changes in phosphorus levels were shown to result in this improved survival — which has not yet been demonstrated — that would result in an "incredible" improvement in outcomes, which would far outweigh any hypothetical long-term risk of bone toxicity.

Bone Study

Hartmut H. Malluche, MD, from the University of Kentucky College of Medicine, in Lexington, and Raymond D. Pratt, MD, vice president, global medical affairs, Shire Pharmaceuticals, in Wayne, Pennsylvania, reported that a study examining renal osteodystrophy among patients with stage 5 CKD and hyperphosphatemia showed that patients treated for 2 years with lanthanum carbonate had better bone formation than patients who received other phosphate binders.

The team randomized 99 patients to standard phosphate binders (primarily calcium-based) or lanthanum carbonate. Patients had bone biopsies at baseline and after 1 and 2 years of treatment. Compared with patients who received standard phosphate binders, those who received lanthanum carbonate had similar serum phosphorus, lower serum calcium, and higher serum parathyroid hormone levels and increased bone formation.

Dr. Sherman commented: "To a large extent, we are fighting the last war when it comes to our concerns about bone issues with lanthanum phosphate binders. Aluminum was toxic to bone and cast a large shadow over nephrologists, who were concerned about phosphate-binding agents." He added that there are no animal or clinical data to suggest that lanthanum is toxic to bone.

Effective Monotherapy

Alastair J. Hutchison, MD, from the Manchester Royal Infirmary, in the United Kingdom, and Dr. Pratt reported that in a 12-week, open-label study, most patients with stage 5 CKD who switched from alternative phosphate binders to lanthanum-carbonate monotherapy achieved reduced serum phosphorus levels. The recommended starting dose for lanthanum carbonate was 1500 mg/day, which could be increased to 4500 mg/day.

Of 367 patients who were enrolled, 274 patients (75%) completed the study. At screening, 57% of patients were taking a single alternative phosphate binder and 41% were on combination binders. The most common binders were calcium carbonate (60%) and sevelamer hydrochloride (56%); 11% of patients were taking aluminum-based binders as part of combination therapy.

After 12 weeks of lanthanum-carbonate monotherapy, more patients met the KDOQI serum phosphorus target.

Serum Phosphate At Baseline and After Switching to 12 Weeks of Lanthanum Carbonate

Baseline Phosphate Binder(s)/ Serum Phosphate Variable
After 12 Weeks of Lanthanum-Carbonate Monotherapy
1 alternative phosphate binder at baseline

Serum P, mg/dL
< .05
Met KDOQI serum P target (% of patients)
< .05
2 phosphate binders at baseline

Serum P, mg/dL
Met KDOQI serum P target (% of patients)

Most patients achieved phosphorus control by taking approximately three 1000-mg tablets oflanthanum carbonate a day. "Changing patients to Fosrenol monotherapy not only reduces serum phosphorus levels but reduces phosphate-binder pill burden," said Dr. Hutchison.

Higher Doses Seem Safe, Effective

Rajnish Mehrotra, MD, from the Los Angeles Biomedical Institute at Harbor-UCLA Medical Center, in Torrance, California, reported that among dialysis patients who had difficulty controlling their serum phosphorus levels with 3000-mg/day lanthanum carbonate, higher doses (3750 or 4500 mg/day) were well tolerated and enabled most patients to achieve control.

A total of 513 patients on maintenance hemodialysis were enrolled at 65 US sites. They underwent a a 0- to 3-week washout from previous binders followed by a 4-week titration phase, during which they received 1500- to 3000-mg/day lanthanum carbonate. The 215 patients (54%) who achieved the KDOQI target range for serum phosphorus continued to receive the same dosage for another 4 weeks. The 142 patients who were not at target were randomized to receive 3000, 3750, or 4500 mg/day of lanthanum carbonate for 4 weeks. At week 8, the serum phosphorus target was achieved by 37% of the patients who received the 3750- or 4500-mg/day doses of lanthanum carbonate, with no associated increase in adverse events throughout the study, which included a 16-week open-label extension after the 8 weeks.

Dr. Sherman said that the apparent safety of using 4500-mg/day lanthanum is important, because a substantial percentage of patients, as shown in this study, do not achieve serum phosphate control.

The studies were sponsored by Shire. Dr. Malluche and Dr. Hutchison are Shire consultants and scientific advisors and received honoraria from the company. Dr. Pratt is a Shire employee. Dr. Mehrota received grant and research support from the National Institutes of Health, Satellite Health, and Shire; is a consultant for Shire and Novartis; and received honoraria from Baxter Health Care.

Renal Week 2006: ASN Annual Meeting: Abstracts F-PO107, PUB341, and F-PO095.


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