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 achieve targeted mean plasma concentrations of 210 and 155 mg/liter during the 7-day period between days 15 and 22. Pharmacokinetic sampling after doses on days 1, 3, 5, and 8 was used to modify weekly suramin doses, beginning on day 15, in an attempt to achieve specific averaged plasma concentrations of 210 and 155 mg/liter. A 200-mg test dose was not effective in prospectively determining individual pharmacokinetic parameters and dosage requirements. Patients with peak plasma suramin concentrations in excess of 350 mg/liter may be more likely to experience neurotoxicity (P = 0.06), but there was no statistically significant effect of peak suramin concentration or of cumulative dose. Biopsy and 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, CYP3A3/4, and CYP2D6 showed no consistent effect of suramin on these enzymes. Although a correlation between creatinine clearance and suramin renal clearance was found (r2 = 0.38; P < 0.00005), there was no correlation 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 treatment.
Hutson
P R
PR
University of Wisconsin Comprehensive Cancer Center, Madison 53792, USA. PRH@pharmacy.wisc.edu
Tutsch
K D
KD
Rago
R
R
Arzoomanian
R
R
Alberti
D
D
Pomplun
M
M
Church
D
D
Marnocha
R
R
Cheng
A L
AL
Kehrli
N
N
Wilding
G
G
D000328:Adult; D000339:Affect; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D001772:Blood Cell Count / Q000187:drug effects; D018394:CA-125 Antigen / Q000097:blood*; D005260:Female; D006454:Hemoglobins / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D013498:Suramin / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D018394:CA-125 Antigen; D006454:Hemoglobins; D013498:Suramin