PHARMACOLOGICAL VARIABLES ASSOCIATED WITH THE DEVELOPMENT OF NEUROLOGIC TOXICITY IN PATIENTS TREATED WITH SURAMIN

Purpose: To describe pharmacologic variables correlated with the development of neurologic toxicity in patients treated with suramin, Methods: Eighty-one patients were treated with suramin in a phase I study. The rate of drug infusion was continuously adjusted to maintain a preassigned plasma suramin concentration (175, 215, or 275 mu g/mL) for a fixed duration (2 to 8 weeks), Results: Eight patients developed grade III/IV neurologic motor impairment (predominantly motor axonal polyneuropathy). All were treated at the 275-mu g/mL concentration. One patient treated at the 215-mu g/mL concentration developed grade II motor dysfunction. In addition, seven of nine patients had sensory symptoms. pharmacologic variables associated with the development of polyneuropathy included total cumulative suramin dose, duration of exposure to plasma concentrations greater than 200 mu g/mL, and area under the curve (AUG) greater than 200 mu g/mL. Conclusion: Significant neurologic toxicity can result from therapy with suramin, even when dosing is designed to avoid exposure to plasma concentrations greater than 350 mu g/mL. Future clinical trials of suramin should be designed in such a way as to limit the total cumulative dose to less than or equal to 157 mg/kg given over a period of greater than or equal to 8 weeks, limit the period of exposure to plasma suramin concentrations greater than 200 mu g/mL to less than or equal to 25 days, and limit the AUC greater than 200 mu g/mL to less than or equal to 48,000 mg . h/L.