Journal of Clinical Oncology, Vol 13, 2187-2195, Copyright © 1995 by American Society of Clinical Oncology
Development and validation of a pharmacokinetically based fixed dosing scheme for suramin
LM Reyno, MJ Egorin, MA Eisenberger, VJ Sinibaldi, EG Zuhowski and R Sridhara
Division of Medical Oncology, University of Maryland Cancer Center, Baltimore 21201, USA.
PURPOSE: We used population pharmacokinetic-parameter estimates and
designed a fixed dosing schedule to maintain plasma suramin concentrations
between 100 and 300 micrograms/mL and then evaluated its performance.
MATERIALS AND METHODS: On day 1, patients received a 200- mg test dose and
1,000-mg/m2 loading dose. On days 2, 3, 4, and 5, patients received 1-hour
infusions of 400, 300, 250, and 200 mg/m2, respectively. Subsequent 1-hour
infusions of 275 mg/m2 were given on days 8, 11, 15, 19, 22, 29, 36, 43,
50, 57, 67, and 78. Therapy was discontinued for dose-limiting toxicity
(DLT) or progressive disease (PD). Patients were to be removed from the
fixed dosing schedule if, after day 5, three consecutive peak plasma
suramin concentrations were greater than 300 micrograms/mL. RESULTS:
Forty-two patients, including 40 with hormone-refractory prostate cancer
(HRPC), received 700 infusions. Forty patients were assessable for
toxicity; 38 were assessable for response. Two patients with preexisting
pulmonary disease died early of respiratory insufficiency. Treatment was
discontinued in five patients due to DLT and in seven due to PD. No patient
had treatment discontinued due to repeated peak plasma suramin
concentrations > or = 300 micrograms/mL. The fixed dosing schedule was
precise, unbiased, and well tolerated. DLT consisted of grade 4
nephrotoxicity (n = 2), neurotoxicity (n = 2), and corticosteroid- induced
psychosis (n = 1). Three patients, who received all 18 doses of suramin per
protocol, developed severe, but not dose-limiting, malaise, fatigue, and
lethargy. Twenty-four of 36 assessable patients with elevated serum
prostate-specific antigen (PSA) levels had a > or = 50% reduction,
lasting more than 4 weeks, and 18 had a > or = 75% reduction, lasting
more than 4 weeks. Twelve of 23 (52%) symptomatic HRPC patients noted a
subjective improvement in pain. There were no measurable responses in four
patients with measurable disease. The estimated median survival time in 38
assessable patients with HRPC was 18.8 months. The estimated median time to
progression in 35 patients, for whom data were available, was 10.1 months.
CONCLUSION: This easily implemented schedule allowed suramin to be
administered safely as an intermittent bolus injection. Toxicity was
manageable and reversible.
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