To define a maximum tolerable dose,
chloroquinoxaline sulfonamide (CQS) was given as a 1-h infusion every 28 days to
cancer patients for whom no effective standard
therapy was available. Doses were escalated in cohorts of at least three patients each. Plasma for characterization of the pharmacokinetics of free and total CQS was obtained during and after the initial infusion and, when possible, during and after subsequent infusions of CQS if the dose had been reduced. A total of 101 courses of CQS in 55 patients were evaluated. Dose levels ranged from 18 to 3,700 mg/m2. The dose-limiting toxicity was
hypoglycemia, first recognized at the 3,700-mg/m2 dose. When dose-limiting
hypoglycemia was recognized, patients were entered at successively lower doses, with close monitoring of plasma
glucose and
insulin concentrations being done in 26 patients. Grade 1-3
hypoglycemia occurred within 4 h of the termination of CQS infusion and cleared by 24 h. Symptomatic
hypoglycemia was more frequent at doses of CQS above 1,000 mg/m2. Concomitant administration of 5%
glucose did not ameliorate the
hypoglycemia associated with CQS doses of > 1,000 mg/m2. The total calorie intake, percentage of ideal body weight, or percentage of weight lost did not explain the incidence or severity of
hypoglycemia in 12 patients in whom these data were obtained. Cardiac
tachyarrhythmias occurred in 7 patients who received CQS at doses of > or = 1,000 mg/m2, and
tachyarrhythmia was associated with
hypoglycemia in 3 patients. Other toxicities were sporadic, but the frequency of toxicity was higher at CQS doses of > or = 1,000 mg/m2. These toxicities included
fever,
rash,
lightheadedness,
leukopenia,
thrombocytopenia,
alopecia,
diarrhea,
nausea, and
vomiting. All toxicities were reversible. Mean peak plasma [CQS] and AUC increased with dose, with a suggestion that peak plasma [CQS] plateaued at higher doses. The decline in plasma [CQS] was fitted to a three-compartment, open linear model. The terminal half-life ranged from 28 to 206 h. Total body clearance ranged from 44 to 881 ml/h with no evidence of saturation. Urinary excretion of the parent compound in 24 h averaged < 5%. CQS not bound to
plasma protein (free CQS) comprised 1%-17% of total plasma CQS and was not related to dose. A relationship was defined between the magnitude of
hypoglycemia and CQS pharmacokinetic parameters. The percentage of decrease in plasma [
glucose], i.e., (predose [
glucose]-nadir [
glucose]/predose [
glucose]) x 100, correlated with both free and total peak plasma [CQS].(ABSTRACT TRUNCATED AT 400 WORDS)