Aredia

Clinical Pharmacology

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Clinical Pharmacology

Aredia

Bone lesion response was radiographically assessed at baseline and at 3, 6, and 12 months. The complete + partial response rate was 33% in Aredia patients and 18% in placebo patients treated with chemotherapy (P=.001). No difference was seen between Aredia and placebo in hormonally-treated patients.

Pain and analgesic scores, ECOG performance status and Spitzer quality of life index were measured at baseline and periodically during the trials. The changes from baseline to the last measurement carried forward are shown in the following table:

Mean Change (Δ) from Baseline at Last Measurement

	Breast Cancer Patients Receiving Chemotherapy					Breast Cancer Patients Receiving Hormonal Therapy
	Aredia®		Placebo		A vs P	Aredia®		Placebo		A vs P
	N	Mean Δ	N	Mean δ	P-Value*	N	Mean Δ	N	Mean δ	P-Value*
Pain Score	175	+0.93	183	+1.69	.050	173	+0.50	179	+1.60	.007
Analgesic Score	175	+0.74	183	+1.55	.009	173	+0.90	179	+2.28	< .001
ECOG PS	178	+0.81	186	+1.19	.002	175	+0.95	182	+0.90	.773
Spitzer QOL	177	-1.76	185	-2.21	.103	173	-1.86	181	-2.05	.409
Decreases in pain, analgesic scores and ECOG PS, and increases in Spitzer QOL indicate an improvement frombaseline. *The statistical significance of analyses of these secondary endpoints of pain, quality of life, and performance status in all three trials may be overestimated since numerous analyses were performed.

Animal Toxicology

In both rats and dogs, nephropathy has been associated with intravenous (bolus and infusion) administration of Aredia.

Two 7-day intravenous infusion studies were conducted in the dog wherein Aredia was given for 1, 4, or 24 hours at doses of 1-20 mg/kg for up to 7 days. In the first study, the compound was well tolerated at 3 mg/kg (1.7 x highest recommended human dose [HRHD] for a single intravenous infusion) when administered for 4 or 24 hours, but renal findings such as elevated BUN and creatinine levels and renal tubular necrosis occurred when 3 mg/kg was infused for 1 hour and at doses of ≥ 10 mg/kg. In the second study, slight renal tubular necrosis was observed in 1 male at 1 mg/kg when infused for 4 hours. Additional findings included elevated BUN levels in several treated animals and renal tubular dilation and/or inflammation at ≥ 1 mg/kg after each infusion time.

Aredia was given to rats at doses of 2, 6, and 20 mg/kg and to dogs at doses of 2, 4, 6, and 20 mg/kg as a 1-hour infusion, once a week, for 3 months followed by a 1-month recovery period. In rats, nephrotoxicity was observed at ≥ 6 mg/kg and included increased BUN and creatinine levels and tubular degeneration and necrosis. These findings were still present at 20 mg/kg at the end of the recovery period. In dogs, moribundity/death and renal toxicity occurred at 20 mg/kg as did kidney findings of elevated BUN and creatinine levels at ≥ 6 mg/kg and renal tubular degeneration at ≥ 4 mg/kg. The kidney changes were partially reversible at 6 mg/kg. In both studies, the dose level that produced no adverse renal effects was considered to be 2 mg/kg (1.1 x HRHD for a single intravenous infusion).

Brand Name: Aredia
Generic Name: Pamidronate Disodium