Pharmacology: Pharmacodynamics: FOSRENOL is indicated for the treatment of hyperphosphataemia. FOSRENOL contains lanthanum carbonate hydrate. The activity of lanthanum carbonate as a phosphate binder is dependent on the high affinity of lanthanum ions, which are released from the carbonate salt in the acid environment of the upper gastrointestinal tract, for dietary phosphate. Insoluble lanthanum phosphate is formed which reduces the absorption of phosphate from the gastro-intestinal tract.
Several studies have shown that lanthanum can be used to control hyperphosphataemia associated with chronic renal failure through dose titration and that effect is maintained with long-term use. A lower incidence of hypercalcaemia was reported with FOSRENOL (0.4%) compared with calcium-based binders (20.2%) in comparative studies.
Serum PTH concentrations may fluctuate depending on a patient's serum calcium, phosphate and vitamin D status. FOSRENOL has not been shown to have any direct effects on PTH secretion.
Clinical Trials: A total of 1130 patients with chronic renal failure treated with maintenance haemodialysis or CAPD were studied in two phase II and two phase III studies (LAM-IV-202, 204, 301 and 302). Three studies were placebo controlled (1 fixed dose and 2 titrated dose designs) and one included calcium carbonate as an active comparator. During these studies, 1016 patients received lanthanum carbonate, 267 received calcium carbonate and 95 received placebo.
The first phase III study (301) was a two-part study designed to assess the reduction of serum phosphate by FOSRENOL compared to calcium carbonate. The study had 2 parts: Part 1 was a 5-week titration phase after randomization to FOSRENOL or calcium carbonate where patients were titrated to a target phosphate level of 1.8 mmol/L. Part 2 was a 20-week maintenance phase where patients maintained their doses of binder and plasma phosphate levels assessed. The study endpoints were % patients achieving target phosphate levels at the end of the titration and maintenance periods. The plasma phosphate levels from this study are presented in Table 1. Serum phosphate levels were reduced to target levels of 1.8 mmol/L at the end of the 5 week titration period, in 58% of the lanthanum group compared with 70% of the calcium carbonate group. Following 25 weeks of treatment, the proportions controlled were 66% (lanthanum carbonate) and 64% (calcium carbonate). (See Table 1.)
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The second Phase III study (302) was a double-blind, placebo controlled study designed to assess the maintenance in reduction in serum phosphate levels after an open-label titration phase with FOSRENOL to achieve a target phosphate concentration of 1.8 mmol/L. This was followed by a 4-week double-blind phase where patients were randomised to continue to receive FOSRENOL or a comparable number of placebo tablets. The endpoint of this study was the plasma phosphate concentrations after 4 weeks of treatment on FOSRENOL or placebo. A total of 93 patients completed the open-label phase and were randomised to FOSRENOL or placebo. The plasma phosphate levels at the end of the open-label titration and at each week of the double-blind study are presented in Table 2. (See Table 2.)
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Hyperphosphataemia: Lanthanum has been demonstrated to be an effective binder of dietary phosphate for use in controlling the hyperphosphataemia of chronic renal failure. Multiple studies have shown that lanthanum can reliably be used to achieve serum phosphate reductions to target levels through dose titration and to effectively maintain control of serum phosphate levels with long-term use. Maintenance of target phosphate levels was shown to be similar between lanthanum and calcium treatments.
The lowest effective dose of lanthanum that is effective in the control of serum phosphate levels was established to be approximately 750 mg/day. Doses of up to 3000 mg lanthanum resulted in a reduction of serum phosphate to within target control levels in most patients.
No difference in level of control was observed between those patients on haemodialysis and those receiving CAPD. In addition no difference in the effectiveness of lanthanum carbonate administration was noted between patients under or over 65 years of age.
Effects on Bone: Overall, FOSRENOL and standard treatments, including calcium carbonate, produced similar effects on the bones of dialysis patients.
Results from histology and histomorphometry of human biopsy samples evaluated to date from the three clinical studies (Study 301 where patients had been treated with lanthanum carbonate for up to 4.5 years, Studies 303 and 307) showed no evidence of osteomalacia or other adverse bone pathology. In Study 303, a randomised study to investigate the effect of FOSRENOL with calcium carbonate, results showed that FOSRENOL produced marginally greater improvements towards normal values than calcium carbonate for many of the bone primary and secondary response variables in addition to the general improvements in bone growth and turnover parameters. In Study 307, a study where patients had been treated for 2 years, no statistical differences in bone parameters between patients randomised to receive standard therapy or FOSRENOL were observed. Analysis of data from paired bone biopsies (at baseline and at one or two years) in patients randomised to either FOSRENOL or calcium carbonate in Study 303 and patients randomised to either FOSRENOL or alternative therapy in Study 307, showed no differences in the development of mineralisation defects between the groups. An analysis of adverse events in the bone study participants in these studies did not show any increase in adverse events related to the musculoskeletal system, including fractures. FOSRENOL, therefore, does not appear to harm bone following treatment for up to 4.5 years.
Pharmacokinetics: As binding between lanthanum and dietary phosphorus occurs in the lumen of the stomach and upper small intestine, the therapeutic effectiveness of FOSRENOL is not dependent on levels of lanthanum in the plasma.
Lanthanum is present in the environment. Measurement of background levels in non-lanthanum treated chronic renal failure patients during Phase III clinical trials revealed concentrations of <0.05 to 0.90 ng/mL in plasma, and <0.006 to 1.02 μg/g in bone biopsy samples.
Absorption: Lanthanum carbonate has low aqueous solubility (<0.01 mg/mL at pH 7.5) and is minimally absorbed following oral administration. Absolute oral bioavailability is estimated to be <0.002% in humans.
In healthy subjects, plasma AUC and Cmax increased as a function of dose, but in a less than proportional manner, after single oral doses of 250 to 1000 mg lanthanum, consistent with dissolution-limited absorption. The apparent plasma elimination half-life in healthy subjects was 36 hours.
In renal dialysis patients dosed for 10 days with 1000 mg lanthanum 3 times daily, the mean (± sd) peak plasma concentration was 1.06 (± 1.04) ng/mL, and mean AUClast was 31.1 (± 40.5) ng.h/mL. Regular blood level monitoring in 1707 renal dialysis patients taking lanthanum carbonate for up to 2 years showed no increase in plasma lanthanum concentrations over this time period.
Distribution: Orally administered lanthanum is distributed predominantly within the gastrointestinal tract. The small fraction absorbed is extensively bound to human plasma proteins (>99.7%), and binding is high capacity and non-specific. In long-term animal studies, at oral doses up to 17 times a human dose of 3000 mg/day, lanthanum concentrations in the majority of tissues were less than 1 μg/g. Concentrations in brain and cerebrospinal fluid (CSF) were below or around the assay quantification limit (0.01 μg/g for brain and 0.05 ng/mL for CSF) and median steady state concentrations were up to 8.2 μg/g in bone, 11.1 μg/g in liver and 2.2 mg/g in the stomach wall. Rodents, but not dogs, treated at doses 4 times the human dose of 3000 mg/day showed submucosal inflammation and epithelial hyperplasia of the stomach. No other adverse effects were associated with these concentrations. Lanthanum levels in these tissues dissipated very slowly after the cessation of oral dosing, with a half-life >26 weeks.
Metabolism: Lanthanum is not metabolised. Studies in chronic renal failure patients with hepatic impairment have not been conducted. In patients with co-existing hepatic disorders at the time of entry into Phase III clinical studies, there was no evidence of increased plasma exposure to lanthanum or worsening hepatic function after treatment with FOSRENOL for periods up to 2 years.
Elimination: Lanthanum is excreted mainly in the faeces (>90%) with only around 0.000031% of an oral dose excreted via the urine in healthy subjects.