Lanthanum carbonate: safety data after 10 years

Alastair J Hutchison, Rosamund J Wilson, Svetlana Garafola, John Brian Copley, Alastair J Hutchison, Rosamund J Wilson, Svetlana Garafola, John Brian Copley

Abstract

Despite 10 years of post-marketing safety monitoring of the phosphate binder lanthanum carbonate, concerns about aluminium-like accumulation and toxicity persist. Here, we present a concise overview of the safety profile of lanthanum carbonate and interim results from a 5-year observational database study (SPD405-404; ClinicalTrials.gov identifier: NCT00567723). The pharmacokinetic paradigms of lanthanum and aluminium are different in that lanthanum is minimally absorbed and eliminated via the hepatobiliary pathway, whereas aluminium shows appreciable absorption and is eliminated by the kidneys. Randomised prospective studies of paired bone biopsies revealed no evidence of accumulation or toxicity in patients treated with lanthanum carbonate. Patients treated with lanthanum carbonate for up to 6 years showed no clinically relevant changes in liver enzyme or bilirubin levels. Lanthanum does not cross the intact blood-brain barrier. The most common adverse effects are mild/moderate nausea, diarrhoea and flatulence. An interim Kaplan-Meier analysis of SPD405-404 data from the United States Renal Data System revealed that the median 5-year survival was 51.6 months (95% CI: 49.1, 54.2) in patients who received lanthanum carbonate (test group), 48.9 months (95% CI: 47.3, 50.5) in patients treated with other phosphate binders (concomitant therapy control group) and 40.3 months (95% CI: 38.9, 41.5) in patients before the availability of lanthanum carbonate (historical control group). Bone fracture rates were 5.9%, 6.7% and 6.4%, respectively. After more than 850 000 person-years of worldwide patient exposure, there is no evidence that lanthanum carbonate is associated with adverse safety outcomes in patients with end-stage renal disease.

Keywords: end-stage renal disease; hyperphosphatemia; lanthanum carbonate; long-term safety; pharmacokinetics; phosphate binder.

© 2016 Shire Development LLC. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.

Figures

Figure 1
Figure 1
Comparison of the pharmacokinetics of lanthanum and aluminium. ESRD, end‐stage renal disease.
Figure 2
Figure 2
Kaplan–Meier analysis of time to all‐cause mortality based on United States Renal Data System data from 2014 (full analysis set). Horizontal reference line shows median survival time. CI, confidence interval.

References

    1. Block GA, Hulbert‐Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am. J. Kidney Dis. 1998; 31: 607–17.
    1. Melamed ML, Eustace JA, Plantinga L et al. Changes in serum calcium, phosphate, and PTH and the risk of death in incident dialysis patients: a longitudinal study. Kidney Int. 2006; 70: 351–7.
    1. Slinin Y, Foley RN, Collins AJ. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS waves 1, 3, and 4 study. J. Am. Soc. Nephrol. 2005; 16: 1788–93.
    1. Young EW, Albert JM, Satayathum S et al. Predictors and consequences of altered mineral metabolism: the Dialysis Outcomes and Practice Patterns Study. Kidney Int. 2005; 67: 1179–87.
    1. Komaba H, Kakuta T, Suzuki H, Hida M, Suga T, Fukagawa M. Survival advantage of lanthanum carbonate for hemodialysis patients with uncontrolled hyperphosphatemia. Nephrol. Dial. Transplant. 2015; 30: 107–14.
    1. Isakova T, Gutierrez OM, Chang Y et al. Phosphorus binders and survival on hemodialysis. J. Am. Soc. Nephrol. 2009; 20: 388–96.
    1. Lopes AA, Tong L, Thumma J et al. Phosphate binder use and mortality among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS): evaluation of possible confounding by nutritional status. Am. J. Kidney Dis. 2012; 60: 90–101.
    1. Cannata‐Andia JB, Fernandez‐Martin JL, Locatelli F et al. Use of phosphate‐binding agents is associated with a lower risk of mortality. Kidney Int. 2013; 84: 998–1008.
    1. Hutchison AJ, Smith CP, Brenchley PE. Pharmacology, efficacy and safety of oral phosphate binders. Nat. Rev. Nephrol. 2011; 7: 578–89.
    1. Albaaj F, Hutchison AJ. Lanthanum carbonate (Fosrenol): a novel agent for the treatment of hyperphosphataemia in renal failure and dialysis patients. Int. J. Clin. Pract. 2005; 59: 1091–6.
    1. Finn WF. Lanthanum carbonate versus standard therapy for the treatment of hyperphosphatemia: safety and efficacy in chronic maintenance hemodialysis patients. Clin. Nephrol. 2006; 65: 191–202.
    1. Hutchison AJ, Maes B, Vanwalleghem J et al. Long‐term efficacy and tolerability of lanthanum carbonate: results from a 3‐year study. Nephron Clin. Pract. 2006; 102: c61–71.
    1. Hutchison AJ, Barnett ME, Krause R, Kwan JT, Siami GA. Long‐term efficacy and safety profile of lanthanum carbonate: results for up to 6 years of treatment. Nephron Clin. Pract. 2008; 110: c15–23.
    1. Al‐Baaj F, Speake M, Hutchison AJ. Control of serum phosphate by oral lanthanum carbonate in patients undergoing haemodialysis and continuous ambulatory peritoneal dialysis in a short‐term, placebo‐controlled study. Nephrol. Dial. Transplant. 2005; 20: 775–82.
    1. Chiang SS, Chen JB, Yang WC. Lanthanum carbonate (Fosrenol) efficacy and tolerability in the treatment of hyperphosphatemic patients with end‐stage renal disease. Clin. Nephrol. 2005; 63: 461–70.
    1. D'Haese PC, Spasovski GB, Sikole A et al. A multicenter study on the effects of lanthanum carbonate (Fosrenol) and calcium carbonate on renal bone disease in dialysis patients. Kidney Int. Suppl. 2003: S73–8.
    1. Finn WF, Joy MS, Hladik G. Efficacy and safety of lanthanum carbonate for reduction of serum phosphorus in patients with chronic renal failure receiving hemodialysis. Clin. Nephrol. 2004; 62: 193–201.
    1. Hutchison AJ, Barnett ME, Krause R, Siami GA. Lanthanum carbonate treatment, for up to 6 years, is not associated with adverse effects on the liver in patients with chronic kidney disease Stage 5 receiving hemodialysis. Clin. Nephrol. 2009; 71: 286–95.
    1. Hutchison AJ, Gill M, Copley JB, Poole L, Wilson RJ. Lanthanum carbonate versus placebo for management of hyperphosphatemia in patients undergoing peritoneal dialysis: a subgroup analysis of a phase 2 randomized controlled study of dialysis patients. BMC Nephrol. 2013; 14: 40.
    1. Joy MS, Finn WF. Randomized, double‐blind, placebo‐controlled, dose‐titration, phase III study assessing the efficacy and tolerability of lanthanum carbonate: a new phosphate binder for the treatment of hyperphosphatemia. Am. J. Kidney Dis. 2003; 42: 96–107.
    1. Mehrotra R, Martin KJ, Fishbane S, Sprague SM, Zeig S, Anger M. Higher strength lanthanum carbonate provides serum phosphorus control with a low tablet burden and is preferred by patients and physicians: a multicenter study. Clin. J. Am. Soc. Nephrol. 2008; 3: 1437–45.
    1. Pennick M, Dennis K, Damment SJ. Absolute bioavailability and disposition of lanthanum in healthy human subjects administered lanthanum carbonate. J. Clin. Pharmacol. 2006; 46: 738–46.
    1. Pierce D, Hossack S, Robinson A, Zhang P, Martin P. Assessment of pharmacodynamic equivalence and tolerability of lanthanum carbonate oral powder and tablet formulations: a single‐center, randomized, open‐label, 2‐period crossover study in healthy subjects. Clin. Ther. 2012; 34: 1290–1300.
    1. Shigematsu T. Multicenter prospective randomized, double‐blind comparative study between lanthanum carbonate and calcium carbonate as phosphate binders in Japanese hemodialysis patients with hyperphosphatemia. Clin. Nephrol. 2008; 70: 404–10.
    1. Sprague SM, Abboud H, Qiu P, Dauphin M, Zhang P, Finn W. Lanthanum carbonate reduces phosphorus burden in patients with CKD stages 3 and 4: a randomized trial. Clin. J. Am. Soc. Nephrol. 2009; 4: 178–85.
    1. Vemuri N, Michelis MF, Matalon A. Conversion to lanthanum carbonate monotherapy effectively controls serum phosphorus with a reduced tablet burden: a multicenter open‐label study. BMC Nephrol. 2011; 12: 49.
    1. Xu J, Zhang YX, Yu XQ et al. Lanthanum carbonate for the treatment of hyperphosphatemia in CKD 5D: multicenter, double blind, randomized, controlled trial in mainland China. BMC Nephrol. 2013; 14: 29.
    1. Canavese C, Mereu C, Nordio M, Sabbioni E, Aime S. Where have all the lanthanum salts gone, long time passing? Kidney Int. 2003; 64: 2327–8.
    1. Canavese C, Mereu C, Nordio M, Sabbioni E, Aime S. Blast from the past: the aluminum's ghost on the lanthanum salts. Curr. Med. Chem. 2005; 12: 1631–6.
    1. Drueke TB. Lanthanum carbonate as a first‐line phosphate binder: the “cons”. Semin. Dial. 2007; 20: 329–32.
    1. Frazao JM, Adragao T. Non‐calcium‐containing phosphate binders: comparing efficacy, safety, and other clinical effects. Nephron Clin. Pract. 2012; 120: c108–19.
    1. Molony DA, Murthy B. Accumulation of metals and minerals from phosphate binders. Blood Purif. 2005; 23 (Suppl 1): 2–11.
    1. Clinical practice guidelines for bone metabolism and disease in chronic kidney disease . The National Kidney Foundation Kidney Disease Outcomes Quality Initative (NFK KDOQI)™. Available from: [Accessed 27 April 2016].
    1. Sprague SM. A comparative review of the efficacy and safety of established phosphate binders: calcium, sevelamer, and lanthanum carbonate. Curr. Med. Res. Opin. 2007; 23: 3167–75.
    1. Damment SJ, Pennick M. Systemic lanthanum is excreted in the bile of rats. Toxicol. Lett. 2007; 171: 69–77.
    1. Floren C, Tekaya L, Escaig F, Labejof L, Mouthon G, Galle P. Analytical microscopy observations of rat enterocytes after oral administration of soluble salts of lanthanides, actinides and elements of group III‐A of the periodic chart. Cell. Mol. Biol. 2001; 47: 419–25.
    1. Damment SJ, Pennick M. Clinical pharmacokinetics of the phosphate binder lanthanum carbonate. Clin. Pharmacokinet. 2008; 47: 553–63.
    1. Drueke TB. Intestinal absorption of aluminium in renal failure. Nephrol. Dial. Transplant. 2002; 17 (Suppl 2): 13–6.
    1. Krewski D, Yokel RA, Nieboer E et al. Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide. J. Toxicol. Environ. Health B Crit. Rev. 2007; 10 (Suppl 1): 1–269.
    1. Lote CJ, Saunders H. Aluminium: gastrointestinal absorption and renal excretion. Clin. Sci. (Lond.) 1991; 81: 289–95.
    1. Savory J, Bertholf RL, Wills MR. Aluminium toxicity in chronic renal insufficiency. Clin. Endocrinol. Metab. 1985; 14: 681–702.
    1. Wilhelm M, Jager DE, Ohnesorge FK. Aluminium toxicokinetics. Pharmacol. Toxicol. 1990; 66: 4–9.
    1. Cannata‐Andia JB, Fernandez‐Martin JL. The clinical impact of aluminium overload in renal failure. Nephrol. Dial. Transplant. 2002; 17 (Suppl 2): 9–12.
    1. Principles of Bone Biology. Waltham, MA, USA: Academic Press, 2008.
    1. Malluche HH, Siami GA, Swanepoel C et al. Improvements in renal osteodystrophy in patients treated with lanthanum carbonate for two years. Clin. Nephrol. 2008; 70: 284–95.
    1. Bronner F, Slepchenko BM, Pennick M, Damment SJ. A model of the kinetics of lanthanum in human bone, using data collected during the clinical development of the phosphate binder lanthanum carbonate. Clin. Pharmacokinet. 2008; 47: 543–52.
    1. Shigematsu T, Tokumoto A, Nakaoka A, Arisaka H. Effect of lanthanum carbonate treatment on bone in Japanese dialysis patients with hyperphosphatemia. Ther. Apher. Dial. 2011; 15: 176–84.
    1. Spasovski GB, Sikole A, Gelev S et al. Evolution of bone and plasma concentration of lanthanum in dialysis patients before, during 1 year of treatment with lanthanum carbonate and after 2 years of follow‐up. Nephrol. Dial. Transplant. 2006; 21: 2217–24.
    1. Persy VP, Behets GJ, Bervoets AR, De Broe ME, D'Haese PC. Lanthanum: a safe phosphate binder. Semin. Dial. 2006; 19: 195–9.
    1. Behets GJ, Verberckmoes SC, Oste L et al. Localization of lanthanum in bone of chronic renal failure rats after oral dosing with lanthanum carbonate. Kidney Int. 2005; 67: 1830–6.
    1. Bervoets AR, Behets GJ, Schryvers D et al. Hepatocellular transport and gastrointestinal absorption of lanthanum in chronic renal failure. Kidney Int. 2009; 75: 389–98.
    1. Yang Z, Schryvers D, Roels F, D'Haese PC, De Broe ME. Demonstration of lanthanum in liver cells by energy‐dispersive X‐ray spectroscopy, electron energy loss spectroscopy and high‐resolution transmission electron microscopy. J. Microsc. 2006; 223: 133–9.
    1. Alfrey AC, LeGendre GR, Kaehny WD. The dialysis encephalopathy syndrome. Possible aluminum intoxication. N. Engl. J. Med. 1976; 294: 184–8.
    1. Rozas VV, Port FK, Rutt WM. Progressive dialysis encephalopathy from dialysate aluminum. Arch. Intern. Med. 1978; 138: 1375–7.
    1. Alfrey AC. Dialysis encephalopathy. Kidney Int. Suppl. 1986; 18: S53–7.
    1. Alfrey AC. Dialysis encephalopathy. Clin. Nephrol. 1985; 24 (Suppl 1): S15–9.
    1. Evans CH. Biochemistry of the Lanthanides. New York: Plenum Press, 1990.
    1. Kato M, Sugihara J, Nakamura T, Muto Y. Electron microscopic study of the blood‐brain barrier in rats with brain edema and encephalopathy due to acute hepatic failure. Gastroenterol. Jpn. 1989; 24: 135–42.
    1. Xu J, Ling EA. Studies of the ultrastructure and permeability of the blood‐brain barrier in the developing corpus callosum in postnatal rat brain using electron dense tracers. J. Anat. 1994; 184 (Pt 2): 227–37.
    1. LaRue B, Hogg E, Sagare A et al. Method for measurement of the blood‐brain barrier permeability in the perfused mouse brain: application to amyloid‐beta peptide in wild type and Alzheimer's Tg2576 mice. J. Neurosci. Methods 2004; 138: 233–42.
    1. Altmann P, Barnett ME, Finn WF. Cognitive function in Stage 5 chronic kidney disease patients on hemodialysis: no adverse effects of lanthanum carbonate compared with standard phosphate‐binder therapy. Kidney Int. 2007; 71: 252–9.
    1. Wesnes KA, Simpson PM, White L, Pinker S. The Cognitive Drug Research Computerized Assessment Systems for Elderly, AAMI & Demented Patients. J Psychopharmacol 1992; 6: 108.
    1. Swainston Harrison T, Scott LJ. Lanthanum carbonate. Drugs 2004; 64: 985–98.
    1. Navaneethan SD, Palmer SC, Craig JC, Elder GJ, Strippoli GF. Benefits and harms of phosphate binders in CKD: a systematic review of randomized controlled trials. Am. J. Kidney Dis. 2009; 54: 619–37.
    1. Zhang C, Wen J, Li Z, Fan J. Efficacy and safety of lanthanum carbonate on chronic kidney disease‐mineral and bone disorder in dialysis patients: a systematic review. BMC Nephrol. 2013; 14: 226.
    1. Cooney DR, Cutshall WD, Madura JA, Winegarner FG. Small bowel obstruction and ileal perforation: complications of uremia. J. Indiana State Med. Assoc. 1976; 69: 781–4.
    1. Kurita N, Uchihara H. Fecalith formation and colonic perforation after lanthanum carbonate granules administration. Am. J. Kidney Dis. 2014; 63: 861–2.
    1. Korzets A. Lanthanum carbonate/oxycodone constipation, peritonitis and perforated colonic diverticulum in an elderly patient: case report. Reactions Weekly 2012; 1421: 34.
    1. Highlights of prescribing information. FOSRENOL (lanthanum carbonate) chewable tablets, for oral use. US Food and Drug Administration. Available from: ,204734s001lbl.pdf (Accessed 8 June 2016).
    1. Cerny S, Kunzendorf U. Images in clinical medicine. Radiographic appearance of lanthanum. N Engl J Med 2006; 355: 1160.
    1. Chuang CL, Chiou SY, Li SY, Jian DY, Chen JY. The case: a peritoneal dialysis patient with an unusual abdominal film. Treatment with lanthanum carbonate. Kidney Int. 2007; 72: 1291–2.
    1. Muller C, Chantrel F, Faller B. A confusional state associated with use of lanthanum carbonate in a dialysis patient: a case report. Nephrol. Dial. Transplant. 2009; 24: 3245–7.
    1. Kato A, Takita T, Furuhashi M. Accumulation of lanthanum carbonate in the digestive tracts. Clin. Exp. Nephrol. 2010; 14: 100–1.
    1. Crush L, O'Connor OJ, Plant W, Clarkson MR, Shanahan F, Maher MM. Perplexing plain abdominal x‐ray. Radiographic opacities were due to the lanthanum. Gut 2011; 60: 218–54.
    1. Makino M, Kawaguchi K, Shimojo H, Nakamura H, Nagasawa M, Kodama R. Extensive lanthanum deposition in the gastric mucosa: the first histopathological report. Pathol. Int. 2015; 65: 33–7.
    1. Haratake J, Yasunaga C, Ootani A, Shimajiri S, Matsuyama A, Hisaoka M. Peculiar histiocytic lesions with massive lanthanum deposition in dialysis patients treated with lanthanum carbonate. Am. J. Surg. Pathol. 2015; 39: 767–71.
    1. Wilson RJ, Johnson S, Marelli C. Lanthanum carbonate versus standard phosphate binder therapy: iron parameters in patients with end‐stage renal disease. Hemodial. Int. 2016; 20: 156.
    1. Alfrey AC. Aluminum toxicity in patients with chronic renal failure. Ther. Drug Monit. 1993; 15: 593–7.
    1. Jeffery EH, Abreo K, Burgess E, Cannata J, Greger JL. Systemic aluminum toxicity: effects on bone, hematopoietic tissue, and kidney. J. Toxicol. Environ. Health 1996; 48: 649–65.
    1. Garbossa G, Galvez G, Castro ME, Nesse A. Oral aluminum administration to rats wih normal renal function. 1. Impairment of erythropoiesis. Hum. Exp. Toxicol. 1998; 17: 312–7.
    1. Cannata‐Andia JB, Fernandez‐Martin JL. The clinical impact of aluminium overload in renal failure. Nephrol. Dial. Transplant. 2002; 17 (Suppl 2): 9–12.
    1. Foley RN, Collins AJ. The USRDS: what you need to know about what it can and can't tell us about ESRD. Clin. J. Am. Soc. Nephrol. 2013; 8: 845–51.
    1. Jamal SA, Vandermeer B, Raggi P et al. Effect of calcium‐based versus non‐calcium‐based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta‐analysis. Lancet 2013; 382: 1268–77.
    1. Moe S, Drueke T, Cunningham J et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2006; 69: 1945–53.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere