Phase I and pharmacokinetic study of a new antineoplastic agent: pyrazine diazohydroxide (NSC 361456).
Pyrazine diazohydroxide (PZDH) is a novel antineoplastic agent that appears to form DNA adducts via the reactive pyrazine diazonium ion and produces substantial antitumor activity in preclinical models. We conducted a phase I trial to determine the maximally tolerated dose of PZDH that could be administered as a 5-min i.v. bolus for 5 consecutive days repeated every 28 days. Thirty-one patients with advanced cancer refractory to standard therapy received a total of 65 cycles of therapy at 7 sequential PZDH dose levels: 18, 36, 45, 56, 75, 100, and 133 mg/m2/day. At the maximally tolerated dose (133 mg/m2/day x 5), all 4 patients experienced grade 3-4 thrombocytopenia, and 3 of 4 had grade 3-4 neutropenia. At the recommended phase II dose (100 mg/m2/day x 5), the median WBC nadir following the first cycle was 2.5 x 10(3)/microliters (range, 0.6-7.6) occurring on day 36, and the median platelet nadir was 87 x 10(3)/microliters (range, 9-155) occurring on day 26. Nausea and vomiting occurred at all dose levels, but were well controlled with ondansetron. No evidence of hepatic, renal, pulmonary, cardiac, venous, dermatological, or neurological toxicity was observed. Pharmacokinetic evaluations were performed on 28 of the 31 patients using an analytical method including derivatization of the parent drug to 2-chloropyrazine. We report the total 2-chloropyrazine, which represents PZDH converted per method plus PZDH converted in vivo. Although the assay quantitation limit is 10 ng/ml, PZDH could only be detected at the first dose level for 30-90 min after the i.v. bolus. Compartmental modeling of the first 4 dose levels was most consistent with a 2-compartment model. Subsequent dose levels revealed a third phase to the plasma decay curve. The area under the plasma drug concentration-time curve increased proportionally with dose; there was no evidence for dose-dependent pharmacokinetics. Pharmacokinetic parameters for 12 patients analyzed by the 3-compartment model revealed an alpha-half-life (t1/2 alpha) of 2.83 +/- 1.57 (mean +/- SD), a t1/2 beta of 11.9 +/- 4.42, and a t1/2 gamma of 161 +/- 47.1 min, with a mean clearance of 1.86 +/- 0.91 liters/min. At the 100- and 133-mg/m2 dose levels, the mean areas under the plasma drug concentration-time curve were 105 and 169 micrograms min/ml, respectively. There was a moderate correlation between body surface area and clearance (r = 0.45, P = 0.015) but a better correlation between weight and clearance (r = 0.53, P = 0.004).(ABSTRACT TRUNCATED AT 400 WORDS)
Vogelzang
N J
NJ
Section of Hematology/Oncology, University of Chicago Pritzker School of Medicine, Illinois 60637-1470.
Mick
R
R
Janisch
L
L
Berezin
F
F
Schilsky
R L
RL
Ratain
M J
MJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013921:Thrombocytopenia / Q000139:chemically induced
D000970:Antineoplastic Agents; D011719:Pyrazines; C051397:pyrazine-2-diazohydroxide