Pharmacology of the Phosphate Binder, Lanthanum Carbonate

Figures & data

Table 1.  Assessment of the safety pharmacology of lanthanum carbonate

Species	Study	Objective	Dose of lanthanum carbonate	Main findings
Cardiovascular system
Dog	SPD/64/PH	Effects on cardiovascular function (anesthetized model)	200, 600, or 2000 mg/kg (single dose, intraduodenal)	No effects of treatment on blood pressure (femoral artery), heart rate, left ventricular pressure, ECG waveform, or blood flow.
Dog	SPD0104	Effects on cardiovascular function (4-week treatment)	0.003, 0.05, or 1 mg/kg/day (28 days, intravenous chloride salt)	No treatment-related effects on ECG waveform. Doses gave plasma lanthanum Cmax values up to 20,000× those in humans (1 ng/mL).
Respiratory system
Dog	SPD/64/PH	Effects on respiratory function (anesthetized model)	200, 600, or 2000 mg/kg (single dose, intraduodenal)	No effects on respiration rate, tidal volume, or minute volume.
Central nervous system
Rat	SPD/41/96	Effects on neurobehavior	2000 mg/kg (single, oral gavage)	Behavior unaffected and no overt signs of toxicity.
Mouse	SPD/42/96	Effects on neurobehavior	500, 1000, or 2000 mg/kg (single, oral gavage)	Behavior unaffected (with the exception of piloerection in two males, 4 h after administration of 2000 mg/kg) and there were no signs of toxicity.
Mouse	SPD/62/PH	Effects on body temperature and behavior	200, 500, or 1000 mg/kg (single, oral gavage)	No effects on body temperature or pharmacological activity detectable by the Irwin test (all doses).
Mouse	SPD/63/PH	Effects on spontaneous motor activity	200, 500, or 1000 mg/kg (single, oral gavage)	Line crossing values comparable with controls; no effect on spontaneous motor activity (all doses).
Mouse	SRU 003/992850	Potential to induce proconvulsant activity	500, 1000, or 2000 mg/kg (single, oral gavage)	No statistically significant proconvulsant activity in either the metrazol- or electroshock-induced tests, compared with the vehicle-treated control group.
Mouse	SRU 005/992851	Potential to induce anticonvulsant activity	500, 1000, or 2000 mg/kg (single, oral gavage)	No significant anticonvulsant activity in either the minimal metrazol or supramaximal electroshock test (all doses).
Dog	SPD/66/TK	Effects on neurobehavior, chronic treatment	200, 600, or 2000 mg/kg/day (52-week treatment, oral capsule)	Assessment included anal sphincter tone, gait, patella reflex, panniculus reflex, pupillary response, ocular cephalic reflex, palpebral reflex, proprioception, righting reflex, withdrawal reflex. No treatment-related findings in the neurotoxicity assessment (all doses).
Mouse	SPD/88/C	Effects on neurobehavior, chronic treatment	100 or 1500 mg/kg/day (62-week treatment, oral gavage)	No behavioral, autonomic, or neurologic effects (Irwin test, all doses).
Gastrointestinal tract
Rat	SPD/47/PH	Effects on charcoal meal transit in the small intestine	200, 500, or 1000 mg/kg (single, oral gavage)	No effects on intestinal motility. At 1000 mg/kg, slight inhibition of gastric emptying.
Rat	SPD/49/PH	Effects on urinary and fecal output	200, 500, or 1000 mg/kg (single, oral gavage)	No diarrhea or abnormal fecal output suggesting no disturbance of intestinal function.
Rat	SPD/48/PH	Effects on gastric acid secretion	200, 500, or 1000 mg/kg (single, oral gavage)	No effect on volume of gastric acid secretion. Reduced acidity of gastric contents by neutralization at 1000 mg/kg.
Rat	SPD/50/PH	Potential to induce lesions in the stomach	200, 500, or 1000 mg/kg (single, oral gavage)	No gastric damage.
Rat	SPD/51/PH	Effects on aspirin-induced gastric damage	200, 500, or 1000 mg/kg (single, oral gavage)	No exacerbation of aspirin-induced gastric damage.

Note: ECG, electrocardiogram.

Figure 1. The effects of lanthanum carbonate and aluminum hydroxide on urinary (A) and fecal (B) excretion of [³²P]-phosphate in rats with normal renal function. Rats (n = 5 per group) were treated with vehicle, lanthanum carbonate, or aluminum hydroxide by oral gavage for 12 days. On day 7, animals received a single oral dose of 11 µCi [³²P]-phosphate. Urine and feces were then collected continuously for 144 h and sample radioactivity was determined. Data are mean ± SD.

Notes: *Denotes p < 0.05 versus lanthanum carbonate and aluminum hydroxide; NS, not significant.

Figure 2. Effect of lanthanum carbonate on phosphate, calcium, and parathyroid hormone (PTH) in rats with normal renal function. Rats (n = 10 per group) were dosed daily by oral gavage for 13 weeks with vehicle or lanthanum carbonate. Blood and urine samples were then collected during fasting conditions and phosphorus, calcium, and PTH levels were determined. Data are presented as mean ± SD.

Note: * and ** Denote p < 0.01 and p < 0.001, respectively, versus vehicle-treated control group.

Figure 3. Effect of lanthanum carbonate on phosphate, calcium, and parathyroid hormone (PTH) in rats with chronic renal failure. Rats (n = 10 per group) underwent 5/6th nephrectomy and were administered vehicle or lanthanum carbonate by oral gavage for 12 weeks. Blood and urine samples were then collected during fasting conditions and levels of phosphorus, calcium, and PTH were determined. Data are presented as mean ± SD.

Note: *Denotes p < 0.05 versus vehicle-treated control group.¹⁶

Figure 4. Relative urinary phosphate-lowering effect of lanthanum carbonate, aluminum hydroxide, calcium carbonate, and sevelamer hydrochloride in rats with chronic renal failure. Rats (n = 10) underwent 5/6th nephrectomy. Following stabilization postsurgery, animals were treated with vehicle or 1000 mg/kg/day of lanthanum carbonate, aluminum hydroxide, calcium carbonate, or sevelamer hydrochloride by oral gavage for 6 weeks. At weeks −3, 0, 2, 4, and 6, 24-h urine samples were collected and analyzed for phosphate levels. Data are presented as mean ± SD.

Source: Adapted from Hutchison.⁷

Note: *Denotes p < 0.01 for least-squares (LS) mean change from baseline versus vehicle-treated control group.

Hutchison AJ. Improving phosphate-binder therapy as a way forward. Nephrol Dial Transplant. 2004;19(Suppl. 1):i19–i24.

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