Clinical Pharmacokinetics of the Phosphate Binder Lanthanum Carbonate

Abstract

Lanthanum carbonate is considered to be the most potent of a new generation of noncalcium phosphate binders used to treat hyperphosphataemia in chronic kidney disease (CKD), a condition associated with progressive bone and cardiovascular pathology and a markedly elevated risk of death. Its phosphate-binding action involves ionic binding and precipitation of insoluble complexes within the lumen of the intestine, thereby preventing absorption of dietary phosphate. While pharmacokinetics have little relevance to the efficacy of lanthanum carbonate, they are of fundamental importance when it comes to evaluating safety. When administered as lanthanum carbonate, the oral bioavailability of lanthanum is low (approximately 0.001%). The small absorbed fraction is excreted predominantly in bile, with less than 2% being eliminated by the kidneys. Predictably, therefore, plasma exposure and pharmacokinetics have been shown to be similar in healthy human volunteers and CKD stage 5 patients. With almost complete plasma protein binding, free lanthanum concentrations in patients at steady state are <3 pg/mL. These properties greatly reduce systemic exposure, tissue deposition and the potential for adverse effects. While lanthanum has a variety of calcium-like actions in vitro, there is little or no evidence that these occur in vivo. This paradox is explained by the very low concentrations of circulating free lanthanum ions, which are many orders of magnitude lower than reported effect concentrations in vitro. Safety pharmacology and toxicology evaluations have failed to reveal any significant calcium-like actions in vivo, despite inclusion of high intravenous doses in some cases.Lanthanum carbonate has a low propensity to cause systemic drug interactions due to its poor absorption. However, the higher concentrations present in the gastrointestinal tract can form chelates with some drugs, such as fluoroquinolones, and reduce their absorption. The improved understanding of the pharmacokinetics of lanthanum that has emerged in recent years has helped to explain why the myriad of calcium-like effects described in vitro for lanthanum have little if any relevance in vivo. The pharmacokinetic investigations of lanthanum carbonate formed an important part of the stringent premarketing safety assessment process and have been influential in reassuring both regulators and physicians that the agent can be used safely and effectively in this vulnerable dialysis population.