Pharmacokinetics of 9-methoxy-N,N-dimethyl-5-nitropyrazolo [3,4, 5-kl]acridine-2(6H)-propanamine (PZA, PD 115934, NSC 366140) in mice: guidelines for early clinical trials1.
Pharmacokinetic studies that consisted of measuring the plasma drug profile, tissue drug distribution, and elimination in urine and feces were performed in female C57BL/6 x DBA/2 (hereafter called B6D2F1) and male B6D2F1A/2 and C57BL/6 x CH3 (hereafter called B6C3F1) mice following treatment with a 1-h i.v. infusion of the PZA, PD115934 (NSC 366140). This drug is the first of a new class of cytotoxic agents and was selected for clinical trials because of both its broad antitumor activity in vivo against murine solid tumors and human xenografts, and its in vivo toxicity profile that was predictable based on drug dose and schedule of administration. The pharmacokinetic results obtained here in mice have been used to facilitate the dose escalations during the Phase I trial and to determine pharmacokinetic drug exposure targets for its acute and sub-acute toxic effects. Plasma samples from three to four mice per time point were pooled, and then individual tissue samples from the same mice were collected at specified times following treatment. All samples were prepared using solid-phase extraction and assayed using high pressure liquid chromatography. The acute dose-limiting toxicity was neurological and occurred immediately after treatment at 300 mg/m2. The peak plasma level range at the acute maximum tolerated dose was 1040-1283 ng/ml. Thus, peak plasma levels <1000 ng/ml were the acute toxicity target. Variations in the area under the plasma drug concentration x the time curve were observed that did not appear to be related to sex or age. The previously defined subacute dose-limiting toxicity was myelosuppression that occurred at a maximum tolerated dose of 600 mg/m2 (300 mg/m2 x 2) in B6D2F1 females. Thus, the area under the plasma drug concentration x the time curve in B6D2F1 females at this dose (1048 microg/ml x min) was the area under the plasma drug concentration x the time curve target. Drug levels were detected at 60 min following treatment in all tissues examined with a plasma:tissue ratio as high as 1:500. The organs with the highest levels were kidney, pancreas, liver, lung, and brain. Fecal excretion was low (range, 0.04-0.20% of the dose administered) and was not clearly different between males and females. Urinary excretion was higher (range, 5-28% of the dose administered) and did show evidence of sex-related differences, with male urinary drug excretion being higher than female urinary drug excretion. The drug was >/=95% protein bound. Preliminary evidence for drug metabolism was found in urine and feces and will be further explored.
Foster
B J
BJ
Wayne State University School of Medicine, Department of Internal Medicine, Division of Hematology and Oncology, Detroit, Michigan 48202-0188, USA.
Wiegand
R A
RA
LoRusso
P M
PM
Baker
L H
LH
D000166:Acridines / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D002986:Clinical Trials as Topic; D017321:Clinical Trials, Phase I as Topic / Q000592:standards; D003433:Crosses, Genetic; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D017410:Practice Guidelines as Topic; D011720:Pyrazoles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D000166:Acridines; D000970:Antineoplastic Agents; D011720:Pyrazoles; C064541:NSC 366140