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Gallium Nitrate for Acute Treatment of Cancer-related Hypercalcemia: Clinicopharmacological and Dose Response Analysis¹

Developmental Chemotherapy [R. P. W., A. S.], Renal/Physiology [N. W. A.], and Endocrine [R. S. B.] Services, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Current treatment of cancer-related hypercalcemia is limited by agents of limited effectiveness or excessive toxicity. Gallium nitrate is a new drug which both inhibits bone resorption and increases calcium content of bone. We have now treated 39 episodes of hypercalcemia with gallium nitrate administered as a continuous i.v. infusion for 5–7 days at 3 daily dose levels (100 and 200 mg/m², and 50 mg/m² by brief infusion followed by 150 mg/m²). Nadir calcium values were significantly lower (9.2 ± 1.5 mg/dl) for patients who received the highest dose relative to patients who received the lowest dose (10.5 ± 1.6 mg/dl, P < 0.001). While the actual percentage of patients who achieved normocalcemia was higher at the highest dose relative to the lowest dose (86 versus 60%), this difference was not statistically significant. Mean serum concentration of inorganic phosphorous declined significantly for all patients from 2.9 ± 0.86 mg/dl at base line to 1.8 ± 0.66 mg/dl (P < 0.001). Pharmacokinetic studies suggested that a threshold plasma gallium concentration of approximately 1 µg/ml must be attained to achieve acute normalization of elevated serum calcium levels. Steady-state plasma gallium levels were attained after 48 h; there was no evidence of drug accumulation in plasma after 2 days. Effects on serum creatinine concentration were negligible, and there were no other toxic reactions. These data confirm preclinical experiments which suggested that inhibition of bone resorption by gallium nitrate is dependent upon the dose and duration of drug exposure. We conclude that gallium nitrate is effective treatment for cancer-related hypercalcemia. The drug is now being evaluated against standard treatment in a randomized, double-blind trial.

¹ Presented in part at the Annual Meeting of the American Society for Clinical Investigation, Washington, DC, April 30, 1983, and the American Society of Clinical Oncology, Los Angeles, CA, May 5, 1986.

² Supported in part by Grant CA-37768 from the National Cancer Institute, NIH. To whom requests for reprints should be addressed, at 1275 York Avenue, New York, NY 10021.

Received 1/10/86. Revised 4/ 1/86. Accepted 4/18/86.

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