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Lanthanum carbonate.

Overview

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Lanthanum is a rare-earth trace metal that naturally occurs in monazite sand and coal (Drueke, 2007). Commercially, lanthanum is a byproduct of the nuclear industry and can be used as a semiconductor in florescent lights and rechargeable batteries (Drueke, 2007). Lanthanum has been recently marketed in Canada as Fosrenol[R]. It is available in 500 mg, 750 mg and 1000 mg chewable tablets (Anon, 2007). Lanthanum carbonate is indicated as a phosphate binder in patients with stage 5 chronic kidney disease (Anon, 2007).

Pharmacodynamic properties

Lanthanum carbonate dissociates in the acid environment of the stomach to release lanthanum ions that bind to form highly insoluble complexes with dietary phosphate. This inhibits the absorption of phosphate. In vitro studies, lanthanum appears to have similar phosphate binding capacity to calcium carbonate and is somewhat superior to sevelamer, particularly at higher pH values (Lacour, Lucas, Auchere, Ruellan, de Serre Patey, & Drueke, 2005; Sprague, 2007). This may be relevant for patients receiving medications that raise stomach pH such as proton-pump inhibitors and H2 antagonists, however, the clinical relevance is unclear.

Pharmacokinetic properties

Absorption: Lanthanum is minimally absorbed in healthy individuals. Bioavailability is stated as < 0.002% in healthy individuals (Anon, 2007). It is important to note, however, that this absorption is enhanced in both uremic animal and human models (Lacour, 2005; Sack, 2002).

Distribution: Lanthanum is highly bound to plasma proteins and, therefore, minimally affected by dialysis. Absorbed lanthanum is distributed to the bone and liver (Anon, 2007). To date, there is no evidence of direct toxicity to these tissues in human clinical studies up to three years in duration (Hutchison, 2006).

Metabolism: Lanthanum is not metabolized.

Elimination: The half-life of lanthanum in the blood is estimated at 53 hours and the half-life in the bone may be as long as 2 to 3.6 years (Anon, 2007).

Efficacy

Summary of short-term studies: A statistically significant decrease in serum phosphate levels was observed in patients receiving lanthanum carbonate at doses of 500 to 3000 mg/day in two-double blind, placebo-controlled phase II studies (Hutchison, 2000; Joy & Finn, 2003). The maximal decrease in serum phosphate levels occurred after three weeks of treatment and were maintained over four to six weeks of treatment. A 13-week phase III randomized, double blind, placebo control, parallel study was conducted in hemodialysis patients (Hutchison, Speake, & Albaaj, 2004). Serum phosphate levels were maintained < 1.9 mmol/L in 59% of patients receiving lanthanum carbonate compared with 23% of the placebo group over four weeks. This difference was statistically significant.

Comparative efficacy: A large prospective, randomized, multicentre, open label, comparator study was completed (Hutchison, Maes, Vanwalleghem, Asmus, Mohamed, Schmieder, et al., 2005). Eight hundred hemodialysis patients were randomized to either lanthanum or calcium carbonate and treated for six months. After nine weeks, both groups had a phosphate < 1.69 mmol/L. Patients who were controlled after nine weeks continued a six-month phase. There were no differences detected during this maintenance phase. However, there were insufficient patients to demonstrate a statistically significant difference if one did exist in the maintenance phase (approximately 57% of enrolled patients).

Summary of long-term studies: Longterm studies are limited, however, an open-label extension study showed that lanthanum carbonate is effective and well-tolerated over three years of treatment, with a low incidence of adverse events and no associated liver toxicity (Hutchison, Maes, Vanwalleghem, Asmus, Mohamed, Schmieder et al., 2006).

Safety and tolerability

As stated, lanthanum carbonate distributes into liver and bone. Clinical studies with up to four years follow-up have not disclosed any hepatotoxic effects of the drug in patients treated with this phosphate binder. However, it is important to note that patient numbers in these trials are small beyond three years of follow-up (Hutchison et al., 2005). Likewise, studies in humans to date have not demonstrated adverse effects of lanthanum carbonate on bone mineralization, however, studies beyond three years of follow-up are limited (D'Haese, Spasovski, Sikole, Hutchison, Freemont, & Sulkova, 2003). Studies with rats have demonstrated the interference of lanthanum with bone mineralization, but this has been attributed to phosphate depletion and not lanthanum itself (Behets, Verberckmoes, Oste, Bervoets, Salome, Cox, et al., 2005). The most common adverse effects that appear to be higher in patients taking lanthanum carbonate compared to standard therapy are nausea, vomiting and diarrhea. These gastrointestinal side effects are reported by 24% to 37% of patients (Finn, 2006). Lanthanum carbonate, a non-calcium phosphate binder, causes significantly less hypercalcemia compared to calcium carbonate 2% versus 54% (Hutchison, 2005).

Pros

Despite our current pharmacologic alternatives indicated for the management of bone mineralization, 59% of patients with stage 5 chronic kidney disease (CKD) do not meet the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) targets for phosphate control (Kimata, Albert, Akiba, Yamazaki, Kawaguchi, Fukuhara, et al., 2007). Adding another agent to the bone mineralization toolkit can only help patients move closer to those goals. An advantage of lanthanum carbonate is various dose formulations and its potent phosphate-lowering capabilities. With its multiple available dosages, most patients could be managed with one tablet three times daily. This could have a significant impact on patient acceptance and compliance. One report demonstrated that up to 70% of dialysis patients are "non-compliant" with standard phosphate binders based on pill counts (Curtin, Svarstad, & Keller, 1999).

Cons

The largest "con" at this point is that there is limited long-term study data and evaluation with the product. Having said this, there does not appear to be significant adverse effects on bone, liver, or central nervous system with this agent in clinical trials up to three years. For patients receiving chronic hemodialysis, the five-year survival is reported to be 39% (USRDS, 2006). Therefore, three-year follow-up is a significant amount of time in the life of a dialysis patient. Post-marketing data will tell the full story.

Conclusion

In the opinion of this author, there is insufficient long-term safety data to recommend lanthanum carbonate as a first-line phosphate binder for the management of hyperphosphatemia in patients receiving dialysis. However, it may be an important addition to the eurotorium of therapies that can be employed to help patients meet NKF KDOQI and Canadian Society of Nephrology (CSN) targets. Lanthanum carbonate may be particularly beneficial for patients who develop adverse effects from standard therapy, or who struggle with compliance and pill burden from standard therapy.

References

Anon. (2007). Fosrenol (lanthanum carbonate) full prescribing information. Shire, Canada. Retrieved January 15, 2008, from http://www.fosrenol.com/PDFs/PrescribingInfo.pdf

Behets, G.J., Verberckmoes, S.C., Oste, L., Bervoets, A.R., Salome, M., Cox, A.G., et al. (2005). Localization of lanthanum in bone of chronic renal failure rats after dosing with lanthanum carbonate. Kidney International, 67, 1830-1836.

Curtin, R.B., Svarstad, B.L., & Keller, T.H. (1999). Hemodialysis patients' non-compliance with oral medications. American Nephrology Nurses Association Journal, 26, 307-316.

De Freitas, D., Donne, R.L., & Hutchison, A.J. (2007). Lanthanum carbonate--A first line phosphate binder. Seminars in Dialysis, 20(4), 325-328.

D'Haese, P.C., Spasovski, G.B., Sikole, A., Hutchison, A., Freemont, T.J., Sulkova, S., et al. (2003). A multicenter study on the effects of lanthanum carbonate (Fosrenol) and calcium carbonate on renal bone disease in dialysis patients. Kidney International, 85, S73-78.

Drueke, T.B. (2007). Lanthanum carbonate as a first-line phosphate binder: The "Cons". Seminars in Dialysis, 20(4), 329-332.

Finn, W.F. (2006). Lanthanum carbonate versus standard therapy for the treatment of hyperphosphatemia: Safety and efficacy in chronic maintenance hemodialysis patients. Clinical Nephrology, 65, 1991-1992.

Finn, W.F., & Joy, M.S. (2005). A long-term, open-label extension study on the safety of treatment with lanthanum carbonate, a new phosphate binder, in patients receiving hemodialysis. Current Medical Research and Opinions, 21, 657-664.

Hutchison, A.J. (2000). Lanthanum carbonate: A novel non-calcaemic phosphate binder in dialysis patients. Nephrology Dialysis Transplantation, 15, A113.

Hutchison, A.J. (2005). Analysis of liver function and hepatobiliary adverse events data from 2000 dialysis patients participating in clinical trials on the new phosphate binder, lanthanum carbonate [abstract]. Nephrology Dialysis Transplantation, 20, (suppl.), v93.

Hutchison, A.J., Maes, B., Vanwalleghem, J., Asmus, G., Mohamed, R., Schmieder R., et al. (2005). Efficacy tolerability, and safety of lanthanum carbonate in hyperphosphatemia: A six-month, randomized, comparative trial versus calcium carbonate. Nephron Clinical Practice, 100, 8-19.

Hutchison A.J., Maes, B., Vanwalleghem, J., Asmus, G., Mohamed, E., Schmieder, R., et al. (2006). Long-term efficacy and tolerability of lanthanum carbonate: Results from a three-year study. Nephron Clinical Practice, 102, c61-c71.

Hutchison, A.J., Speake, M., & Albaaj, F. (2004). Reducing high phosphate levels in patients with chronic renal failure undergoing dialysis, a four-week, dose-finding, open label study with lanthanum carbonate. Nephrology Dialysis Transplantation, 19, 1902-1906.

Joy, M.S., & Finn, W.F. (2003). LAM study group. Randomized, double blind, placebo-controlled, dose titration: Study assessing the efficacy and tolerability of lanthanum carbonate (FOSRENOL): A new phosphate binder for the treatment of hyperphosphatemia. American Journal of Kidney Diseases, 42(1), 96-107.

Kimata, N., Albert, J.M., Akiba, T., Yamazaki, S., Kawaguchi, Y., Fukuhara, S., et al. (2007). Association of mineral metabolism factors with all-cause and cardiovascular mortality in hemodialysis patients: The Japan dialysis outcomes and practice patterns study. Haemodialysis International, 11(3), 340-348.

Lacour, B., Lucas, A., Auchere, D., Ruellan, N., de Serre Patey, N.M., & Drueke, T.B. (2005). Chronic renal failure is associated with increased tissue deposition of lanthanum after 28-day oral administration. Kidney International, 67, 1062-1069.

Loghman-Adham, M. (2003). Safety of new phosphate binders for chronic renal failure. Drug Safety, 26(15), 1093-1115.

Sack, M. (2002, November). Fosrenol (lanthanum carbonate) is well-tolerated in patients requiring hemodialysis: Results of a phase I clinical trial. Paper presented at the annual meeting of the American Society of Nephrology Annual Meeting, Philadelphia, PA.

Sprague, S.M. (2007). A comparative review of the efficacy and safety of established phosphate binders: calcium, sevelamer, and lanthanum carbonate. Current Medical Research and Opinions, 23(12), 3167-3175.

Swainston Harrison, T., & Scott, L.J. (2004). Lanthanum carbonate. Drugs, 64(9), 985-996.

U.S. Renal Data System. (2006). Morbidity and mortality. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Retrieved January 30, 2008, from http://www.usrds.org/2007/pdf/06_hosp_morte_07.pdf

By Dr. Jennifer Ryan, BSc(Pharm), Pharm D,ACPR, Clinical Manager, Pharmacy Services, Renal Pharmacist, Atlantic Health Sciences Corporation, Saint John, NB
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Author:Ryan, Jennifer
Publication:CANNT Journal
Article Type:Disease/Disorder overview
Geographic Code:1CANA
Date:Jan 1, 2008
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