Authors: Bronner, Felix¹; Slepchenko, Boris M.¹; Pennick, Michael²; Damment, Stephen J.P.²

Source: Clinical Pharmacokinetics, Volume 47, Number 8, 2008 , pp. 543-552(10)

Publisher: Adis International

Abstract:

Objective: Lanthanum carbonate (Fosrenol^®) is a non-calcium phosphate binder that controls hyperphosphataemia without increasing calcium intake above guideline targets. The biological fate and bone load of lanthanum were modelled with the aid of a four-compartment kinetic model, analogous to that of calcium.

Methods: The model used data from healthy subjects who received intravenous lanthanum chloride or oral lanthanum carbonate, and bone lanthanum concentration data collected from dialysis patients during three long-term trials (up to 5 years).

Results: Infusion of lanthanum chloride or ingestion of lanthanum carbonate led to a rapid rise in plasma lanthanum concentrations, followed by an exponential decrease. Comparison of oral and intravenous exposure confirmed that lanthanum is very poorly absorbed. On a typical intake of lanthanum (3000 mg/day as lanthanum carbonate), the rate of absorption was calculated as 2.2 μg/h, with a urinary excretion rate constant of 0.004-0.01 h⁻¹. The faecal content of endogenous lanthanum was estimated to be 8- to 20-fold greater than that of urine, compared with a ratio of only about 1 for calcium. The model predicts that upon multiple dosing, plasma lanthanum concentrations rise rapidly to a near plateau and then increase by about 3% per year. However, this small change is obscured by the variability of the study data, which show that a plateau is rapidly attained by 2 weeks and is thereafter maintained for at least 2 years. The initial deposition rate of lanthanum in bone was 1 μg/g/year and, after 10 years of lanthanum carbonate treatment, the model predicts a 7-fold increase in total bone lanthanum (from 10 mg to 69 mg [from 1 μg/g wet weight to 6.6 μg/g wet weight]), with lanthanum cleared after cessation of treatment at 13% per year. The model indicates that lanthanum flow from bone surface to bone interior is much lower than that of calcium.

Conclusion: Bone is the major reservoir for metals, but bone lanthanum concentrations are predicted to remain low after long-term treatment because of very poor intestinal absorption.

Keywords: Bone; Hyperphosphataemia; Lanthanum carbonate; Pharmacokinetic modelling; Phosphate binders; Renal failure

Document Type: Research article

Affiliations: 1: 1 University of Connecticut Health Center, Farmington, Connecticut, USA 2: 2 Shire Pharmaceuticals, Basingstoke, UK

Publication date: 2008-01-01

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