A model of the kinetics of lanthanum in human bone, using data collected during the clinical development of the phosphate binder lanthanum carbonate

Objective: Lanthanum carbonate (Fosrenol (R)) 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 mu g/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 mu g/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 mu g/g wet weight to 6.6 mu g/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.