The clinical use of lanthanum carbonate

The clinical use of lanthanum carbonate

The chemical element lanthanum has the symbol La and atomic number 57. It is a silvery white metal and represents the start of the lanthanoid series (Ln).

Lanthanum has two oxidation states, +II and +III, and the latter is the more stable one. The electronic configuration of the resulting La³⁺ ion is [Xe]4f⁰. Lanthanum burns in the presence of air and forms lan-thanum(III) oxide:

4La + 3O₂ → 2La₂O₃

Lanthanum reacts with water with the formation of lanthanum hydroxide owing to the electropositive nature of the metal. It also reacts with halogens and forms the respective lanthanum halide salt.

Lanthanum carbonate La₂(CO₃)₃ see Figure 9.2 is the only lanthanum salt approved for clinical use. It is used in the managementof hyperphosphataemia, which is defined as high levels of phosphate in the serum blood (Figure 9.3).

2La + 6H₂O → 2La(OH)₃ + 3H₂

2La + 3Cl₂ → 2LaCl₃

Patients with end-stage renal failure (ESRF) often present high levels of phosphate in the serum as a result of the failure of the kidneys. The serum phosphate level of a healthy human is in the range 0.8–1.5 mmol/l , whereas this level is significantly increased in patients with kidney failure. High phosphate levels are linked to a decrease of calcium serum levels and the release of the so-called parathyroid hormone (PTH). This can manifest itself in renal osteodystrophy, which can have severe pathological consequences such as bone malfunction. Also, increased levels of PTH are observed, which can lead to secondary calcification of muscles and vascular tissue. Nearly half of the deaths of dialysis patients with ESRF are due to cardiac events.

The average phosphate intake ranges from 1000 to 1500 mg/day. In a healthy human, phosphate is absorbed in the gastrointestinal (GI) tract and excreted via the kidneys. In patients with ESRF, phosphate excretion via the kidneys is reduced and therefore accumulates in the serum. A common treatment option includes the binding of phosphate already in the GI tract before it can enter the blood stream. The ideal phosphate binder should bind phosphate with high affinity, should not be absorbed in the GI tract and should be excreted via the faeces. Aluminium salts were used until the early 1980s as phosphate binders. Aluminium phosphate is readily formed but not absorbed. Unfortunately, the aluminium salt (aluminium hydroxide) itself is absorbed in the GI tract and has been found to be toxic. Specific toxicity to the central nervous system (CNS) was observed.

As an alternative treatment option, calcium salts were and still are used as phosphate binders. Calcium salts, such as calcium acetate and calcium carbonate, are very successful treatment options especially in patients undergoing dialysis. The main issue is that calcium ions can be absorbed and this can lead to hypercalcaemia, which is defined as high levels of serum calcium ions. This can further increase the risk of tissue calcification and cardiac events.

Further research has led to a variety of drugs, with sevelamer hydrochloride being one of the most suc-cessful ones. Sevelamer is a hydrogel containing cross-linked polyallylamine chains. The negatively charged phosphate can be bound to the positively charged amine groups of the hydrogel in the intestines and removed via the faeces.

Furthermore, lanthanum carbonate has been successfully studied as a phosphate binding agent. Lanthanum carbonate fulfils the criteria for a good phosphate binder as stipulated above: nontoxic, rapid binding of phos-phate, not absorbed in the GI tract and easily excreted. A comparative study of a variety of lanthanum salts showed that La₂CO₃⋅4H₂O has the best phosphate binding properties at a variety of pHs. This means that phosphate can be bound in the stomach (very low pH) and the complex remains intact whilst travelling through the GI tract where the pH is higher. Pharmacological studies have shown that lanthanum carbonate is poorly absorbed when administered orally and that more than 90% is excreted via the faeces. No specific toxicity has been observed either. Lanthanum carbonate hydrate is marketed under the name Fosrenol and has received approval in Europe and the United States for its clinical use in patients with chronic renal failure .

Lanthanum carbonate hydrate is usually given with an initial dose of 0.75–2.25 g of elemental lanthanum in divided doses with meal. The dose needs to be reviewed every 2–3 weeks until a maintenance dose (1.5–3 g) is achieved. Patients should be advised to chew the tablets before swallowing. Most common side effects include disturbances of the GI tract, resulting in diarrhoea and constipation .