Pharmacometric analysis of the effect of furosemide on suramin pharmacokinetics.
STUDY OBJECTIVE: To characterize the effects of furosemide on the pharmacokinetics of suramin, a renally eliminated investigational antineoplastic agent. DESIGN: Retrospective population pharmacokinetic analysis. SETTING: Government biomedical research facility. PATIENTS: Twenty-six men with hormone-refractory prostate cancer and one with adrenocortical carcinoma. INTERVENTIONS: Patients received suramin by continuous or intermittent infusion with and without concomitant furosemide. MEASUREMENTS AND MAIN RESULTS: Optimum suramin regimens were achieved by adaptive feedback control, and pharmacokinetic data were collected both in the presence and absence of furosemide. Suramin concentrations were determined by high-performance liquid chromatography (coefficient of variation < 8%). Suramin concentrations were fit to a three-compartment linear model with six coefficients and two rate inputs, which allowed furosemide to affect suramin pharmacokinetics. Individual and population parameter estimates were determined using the iterative two-stage approach. Concomitant furosemide was associated with a median decrease in total body clearance of suramin by 36% (range 0-63%, p < 0.0001). No other parameter was significantly altered, and there was no trend for change in any pharmacokinetic value with time. Suramin plasma concentrations were simulated with and without prolonged furosemide therapy in 26 patients for 12 weeks. The average suramin concentration increased by greater than 33% in 12 patients; 2 patients had a greater than 67% increase in this extreme case model. CONCLUSION: Coadministration of furosemide with suramin can cause an increase in suramin concentrations; however, due to suramin's long half-life, its rate of accumulation is very slow. Nonetheless, in individuals receiving suramin by nonadaptive control, appropriate precautions should be taken when prolonged furosemide therapy is begun.