Patients with end stage renal disease (ESRD) can develop hyperphosphatemia that may be associated with secondary hyperparathyroidism and elevated calcium phosphate product. Elevated calcium phosphate product increases the risk of ectopic calcification. Treatment of hyperphosphatemia usually includes all of the following: reduction in dietary intake of phosphate, removal of phosphate by dialysis and inhibition of intestinal phosphate absorption with phosphate binders. FOSRENOL® does not contain calcium or aluminum.
Lanthanum carbonate dissociates in the acid environment of the upper GI tract to release lanthanum ions that bind dietary phosphate released from food during digestion. FOSRENOL® inhibits absorption of phosphate by forming highly insoluble lanthanum phosphate complexes, consequently reducing both serum phosphate and calcium phosphate product.
In vitro studies have shown that in the physiologically relevant pH range of 3 to 5 in gastric fluid, lanthanum binds approximately 97% of the available phosphate when lanthanum is present in a two-fold molar excess to phosphate. In order to bind dietary phosphate efficiently, lanthanum should be administered with or immediately after a meal.
Following single or multiple dose oral administration of FOSRENOL® to healthy subjects, the concentration of lanthanum in plasma was very low (bioavailability <0.002%). Following oral administration in ESRD patients, the mean lanthanum Cmax was 1.0 ng/mL. During long-term administration (52 weeks) in ESRD patients, the mean lanthanum concentration in plasma was approximately 0.6 ng/mL. There was minimal increase in plasma lanthanum concentrations with increasing doses within the therapeutic dose range. The effect of food on the bioavailability of FOSRENOL® has not been evaluated, but the timing of food intake relative to lanthanum administration (during and 30 minutes after food intake) has a negligible effect on the systemic level of lanthanum.
In vitro, lanthanum is highly bound (>99%) to human plasma proteins, including human serum albumin,α1-acid glycoprotein, and transferrin. Binding to erythrocytes in vivo is negligible in rats.
In 105 bone biopsies from patients treated with FOSRENOL® for up to 4.5 years, rising levels of lanthanum were noted over time. Estimates of elimination half-life from bone ranged from 2.0 to 3.6 years. Steady state bone concentrations were not reached during the period studied.
In studies in mice, rats and dogs, lanthanum concentrations in many tissues increased over time and were several orders of magnitude higher than plasma concentrations (particularly in the GI tract, bone and liver). Steady state tissue concentrations in bone and liver were achieved in dogs between 4 and 26 weeks. Relatively high levels of lanthanum remained in these tissues for longer than 6 months after cessation of dosing in dogs. There is no evidence from animal studies that lanthanum crosses the blood-brain barrier.
Lanthanum is not metabolized and is not a substrate of CYP450. In vitro metabolic inhibition studies showed that lanthanum at concentrations of 10 and 40μg/ml does not have relevant inhibitory effects on any of the CYP450 isoenzymes tested (1A2, 2C9/10, 2C19, 2D6, and 3A4/5). Lanthanum was cleared from plasma following discontinuation of therapy with an elimination half-life 53 hours.
No information is available regarding the mass balance of lanthanum in humans after oral administration. In rats and dogs, the mean recovery of lanthanum after an oral dose was about 99% and 94% respectively and was essentially all from feces. Biliary excretion is the predominant route of elimination for circulating lanthanum in rats. In healthy volunteers administered intravenous lanthanum as the soluble chloride salt (120 μg), renal clearance was less than 2% of total plasma clearance. Quantifiable amounts of lanthanum were not measured in the dialysate of treated ESRD patients.
In Vitro- Drug Interactions:
Gastric Fluid: The potential for a physico-chemical interaction (precipitation) between lanthanum and six commonly used medications (warfarin, digoxin, furosemide, phenytoin, metoprolol, and enalapril) was investigated in simulated gastric fluid. The results suggest that precipitation in the stomach of insoluble complexes of these drugs with lanthanum is unlikely.
In Vivo- Drug Interactions:
Lanthanum carbonate is neither a substrate nor an inhibitor of CYP450 enzymes.
The absorption of a single dose of 1000 mg of FOSRENOL® is unaffected by co-administration of citrate. No effects of lanthanum were found on the absorption of digoxin (0.5-mg), metoprolol (100-mg), or warfarin (10-mg) in healthy subjects co-administered lanthanum carbonate (three doses of 1000 mg on the day prior to exposure and one dose of 1000 mg on the day of coadministration). Potential pharmacodynamic interactions between lanthanum and these drugs (e.g., bleeding time or prothrombin time) were not evaluated. None of the drug interaction studies was done with the maximum recommended therapeutic dose of lanthanum carbonate. No drug interaction studies assessed the effects of drugs on phosphate binding by lanthanum carbonate.