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A dose escalation study to determine the toxicity and maximally tolerated dose of foscarnet
E A Seidel1, S Koenig, M A Polis
1Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892.
Objective:
To determine the maximum tolerated dose of intravenous foscarnet (trisodium phosphonoformate hexahydrate); and to examine antiviral activity at plasma levels shown to inhibit HIV-1.
Design:
Dose escalation study in three male subjects with AIDS who received foscarnet by continuous intravenous infusion at a dose of 200 mg/kg per day, after a 20 mg/kg loading dose. The dose was increased until a plasma level > 150 micrograms/ml was attained.
Results:
Foscarnet was discontinued due to progressive renal insufficiency in all three patients (days 11, 19, and 21). Renal function normalized in all three, and no adverse sequelae due to foscarnet were observed at 1 year of follow-up. A seizure was observed in one patient on day 19. Maximum daily doses of foscarnet achieved were 395 mg/kg, 389 mg/kg, and 523 mg/kg. No changes in serum Ca2+, Mg2+, or PO4- were observed.
Conclusions:
Renal effects and toxicity of foscarnet in evolving renal insufficiency is self-limiting and reversible when the drug is discontinued. Incremental increases in dose can result in rapid rises in the plasma level with renal failure and may be compounded by concomitant medications and underlying illnesses.