Summary
Abstract
Orally administered lanthanum carbonate (Fosrenol®) dissociates in the acid environment of the upper gastrointestinal tract to release the cation lanthanum, which then binds dietary phosphate.
Lanthanum carbonate was effective in reducing levels of serum phosphate and serum calcium × phosphate product and then maintaining these levels within target ranges for up to 6 years in adult patients with end-stage renal disease (ESRD) on haemodialysis or peritoneal dialysis. The reduction in serum phosphate levels with lanthanum carbonate was generally similar to that with calcium carbonate or sevelamer hydrochloride. This agent was generally well tolerated, with the most frequently reported adverse events being gastrointestinal in nature and occurring at a similar rate to that with calcium carbonate. However, lanthanum carbonate was associated with fewer episodes of hypercalcaemia than calcium carbonate. Overall, lanthanum carbonate is a valuable option for the reduction of serum phosphate levels in patients with ESRD on haemodialysis or peritoneal dialysis.
Pharmacological Properties
Lanthanum carbonate dissociates in the acid environment of the upper gastrointestinal tract to release the trivalent cation lanthanum, which binds with high affinity to dietary phosphate in the stomach and upper small intestine, forming insoluble lanthanum phosphate.
Lanthanum carbonate reduces daily phosphate absorption. In patients with chronic kidney disease with residual kidney function, the decrease in urinary phosphate excretion (≈300mg/day) achieved with lanthanum carbonate ≤3000mg/day was estimated to be equivalent to about one-third of the daily phosphate absorption.
Lanthanum carbonate was not associated with detrimental effects on bone-cell activity, according to paired-bone biopsy studies of up to 2 years duration in patients with ESRD. With lanthanum carbonate versus comparator phosphate binder therapy, the percentage of patients with improved bone turnover after 1 year, but not 2 years, was significantly higher, and the percentage of patients with reduced bone volume was significantly lower after 2 years.
Lanthanum does not appear to cross the blood-brain barrier, according to data from animal studies. In patients with ESRD undergoing haemodialysis, there was no significant difference between lanthanum carbonate and alternative phosphate binder therapy in the decline in cognitive function that occurred over a 2-year period.
Systemic absorption of lanthanum carbonate is minimal (absolute bioavailability <0.002%). In patients with ESRD administered lanthanum carbonate 3000 mg/day for 10 days, the mean maximum plasma concentration of lanthanum was 1.0 ng/mL. Plasma concentrations of lanthanum did not increase with long-term (up to 6 years) administration of lanthanum carbonate. Bone biopsies taken from patients with ESRD who were treated with lanthanum carbonate for up to 4.5 years indicated an increase in bone lanthanum concentrations over the treatment phase (maximum concentration in any individual patient ≈10μg/g wet weight bone). After treatment cessation, lanthanum loss from bone was estimated to be ≈13% per year. In long-term animal studies, lanthanum concentrations increased over time in several tissues, including the liver; however, there was no evidence of adverse effects of this agent on the liver in clinical studies in which patients with ESRD received up to 6 years of lanthanum carbonate treatment.
Lanthanum is not metabolized and is not a substrate of cytochrome P450 enzymes. The mean elimination half-life was 52 hours in patients with ESRD. Lanthanum carbonate is mainly excreted via the biliary route.
Therapeutic Efficacy
In short-term, randomized, double-blind, multicentre trials in patients with ESRD on stable maintenance haemodialysis or peritoneal dialysis, lanthanum carbonate ≤3000 mg/day was effective in reducing serum phosphate and calcium × phosphateproduct levels and then maintaining these levels at target, while an increase in both these measures occurred with placebo. In a short-term, randomized, double-blind, multicentre trial in Japanese patients with ESRD in which phosphate binder dosages were titrated to achieve target serum phosphate levels, lanthanum carbonate 750–2250 mg/day was noninferior to calcium carbonate 1500–4500 mg/day in reducing serum phosphate levels. In another short-term, fixed-dosage, randomized, open-label, crossover trial, lanthanum carbonate 2250–3000 mg/day was not significantly different to sevelamer hydrochloride 4800–6400 mg/day in reducing serum phosphate levels in patients with ESRD on stable maintenance dialysis, according to an analysis of the intent-to-treat population (primary analysis). If the completer population of this study was analysed, then lanthanum carbonate was more effective than sevelamer hydrochloride.
In randomized, open-label trials in adult patients with ESRD receiving maintenance haemodialysis, lanthanum carbonate 375–3000 mg/day was as effective in controlling serum levels of phosphate and calcium × phosphate product as conventional phosphate binders in a 24-month study and as calcium carbonate in 6-and 12-month studies. Extension studies demonstrated that control of serum phosphate and serum calcium × phosphate product levels was maintained for up to 6 years with lanthanum carbonate.
Tolerability
Lanthanum carbonate was generally well tolerated in short- and long-term clinical studies, with the most common adverse events being gastrointestinal (e.g. nausea, vomiting, diarrhoea, abdominal pain and constipation) and occurring with a similar incidence to that with other phosphate binders (including sevelamer hydrochloride and calcium-based binders). These adverse events were minimized by taking lanthanum carbonate with food, and generally abated over time with continued administration. The incidence of treatment-related adverse events did not increase with increased exposure to lanthanum carbonate, with no new or unexpected adverse events being reported in an extension study in which patients with ESRD received up to 6 years of treatment with this agent. Lanthanum carbonate was associated with fewer episodes of hypercalcaemia than calcium carbonate. With up to 6 years of lanthanum carbonate treatment, the incidence of fractures was low (4.3%).
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Various sections of the manuscript reviewed by: M. Emmett, Department of Internal Medicine, Baylor University Medical Center, Dallas, Texas, USA; D.J. Goldsmith, Renal Unit, Guy’s Hospital and St Thomas’ Hospital, London, UK; A.J. Hutchison, Manchester Royal Infirmary, Manchester, UK; K.J. Martin, Department of Internal Medicine, Saint Louis University, St Louis, Missouri, USA; R. Mehrotra, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA; G.A. Siami, Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Data Selection
Sources: Medical literature published in any language since 1980 on ‘lanthanum carbonate’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: MEDLINE, EMBASE and AdisBase (a proprietary database) search terms were ‘lanthanum carbonate’ and ‘hyperphosphataemia’. Searches were last updated 15 October 2009.
Selection: Studies in patients with end-stage renal disease who received lanthanum carbonate. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Lanthanum carbonate, end-stage renal disease, hyperphosphataemia, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.
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Curran, M.P., Robinson, D.M. Lanthanum Carbonate. Drugs 69, 2329–2349 (2009). https://doi.org/10.2165/11202610-000000000-00000
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DOI: https://doi.org/10.2165/11202610-000000000-00000