Clinical pharmacology of 11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo (7.4.1.0(2,7).0(10,12) tetradeca-2,4,6-trien-6,9-diyl diacetate (FK 973).
FK 973, a novel substituted dihydrobenzoxazine structurally similar to mitomycin C, is a derivative of the product isolated from Streptomyces sandaensis. In vitro and in rodents, it is a potent antitumor agent. During Phase I clinical trials, we evaluated the pharmacologic properties of FK 973 in eight adenocarcinoma patients after a 30-min i.v. infusion of doses ranging from 7 to 45mg/m2. An established enzyme immunoassay that measures the stable deacetylated active metabolite FR66980 showed that the plasma drug levels declined biphasically with a terminal half life (t1/2 beta) of 4.7 +/- 1.6hr (mean +/- S.D.) The total clearance rate was 438 +/- 113ml/(min/m2). Both the maximum plasma drug concentrations (Cmax) and the area under the concentration-versus-time curve (AUC) were dose related. In addition to nausea and vomiting, alopecia, and myelosuppression, three patients experienced a delayed vascular-leak syndrome. The 3 patients had received doses among the highest studied, and the toxicity appeared to be dose related and cumulative. The evidence suggests that higher doses generated higher Cmax and AUC values, which may be correlated with toxic effects.
Department of Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
D H
DH
Ho
R
R
Pazdur
N S
NS
Brown
W P
WP
Covington
M N
MN
Raber
I H
IH
Krakoff
D000107:Acetylation; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000378:metabolism / Q000648:ultrastructure; D010078:Oxazines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D000970:Antineoplastic Agents; D010078:Oxazines; C081770:FR 66980; C054974:FK 973