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) 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 microg/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 microg/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 microg/g wet weight to 6.6 microg/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.


CONCLUSIONS
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.
Bronner
Felix
F
University of Connecticut Health Center, Farmington, Connecticut 06030-6125, USA. bronner@neuron.uchc.edu
Slepchenko
Boris M
BM
Pennick
Michael
M
Damment
Stephen J P
SJ
D000284:Administration, Oral; D001842:Bone and Bones / Q000378:metabolism*; D002118:Calcium / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D006801:Humans; D007275:Injections, Intravenous; D007811:Lanthanum / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008954:Models, Biological; D010710:Phosphates / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D006435:Renal Dialysis; D013997:Time Factors
D010710:Phosphates; C119467:lanthanum carbonate; D007811:Lanthanum; D002118:Calcium