RENAL CLEARANCE, TISSUE DISTRIBUTION, AND CA-125 RESPONSES IN A PHASE-I TRIAL OF SURAMIN

Suramin was administered to 49 patients in a Phase I cancer trial with real-time pharmacokinetic monitoring and dose individualization to ac hieve targeted mean plasma concentrations of 210 and 155 mg/liter duri ng the 7-day period between days 15 and 22, Pharmacokinetic sampling a fter doses on days 1, 3, 5, and 8 was used to modify weekly suramin do ses, beginning on day 15, in an attempt to achieve specific averaged p lasma concentrations of 210 and 155 mg/liter, A 200-mg test dose was n ot effective in prospectively determining individual pharmacokinetic p arameters and dosage requirements, Patients with peak plasma suramin c oncentrations in excess of 350 mg/liter may be more likely to experien ce neurotoxicity (P = 0.06), but there was no statistically significan t effect of peak suramin concentration or of cumulative dose. Biopsy a nd autopsy tissue samples demonstrated low penetration of suramin into brain tissue and muscle but good penetration into prostate and other visceral organs. Prospective use of surrogate substrates for CYP1A2, C YP3A3/4, and CYP2D6 showed no consistent effect of suramin on these en zymes, Although a correlation between creatinine clearance and suramin renal clearance was found (r(2) = 0.38; P < 0.00005), there was no co rrelation between creatinine clearance and total suramin clearance (P = 0.21), No suramin dose modification for renal or hepatic dysfunction can be supported at this time. Three of four ovarian cancer patients demonstrated a drop in CA-125 serum concentrations during suramin trea tment.