CLINICAL-PHARMACOLOGY OF MOYLOXYMETHYL-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 Streptomyce s sandaensis. In vitro and in rodents, it is a potent antitumor agent. During Phase I clinical trials, we evaluated the pharmacologic proper ties of FK 973 in. eight adenocarcinoma patients after a 30-min i.v. i nfusion of doses ranging from 7 to 45mg/m2. An established enzyme immu noassay that measures the stable deacetylated active metabolite FR6698 0 showed that the plasma drug levels declined biphasically with a term inal half life (t1/2beta) of 4.7 +/-1.6hr (mean +/- S.D.) The total cl earance rate was 438 +/-113ml/(min/m2). Both the maximum plasma drug c oncentrations (C(max)) and the area under the concentration-versus-tim e curve (AUC) were dose related. In addition to nausea and vomiting, a lopecia, and myelosuppression, three patients experienced a delayed va scular-leak syndrome. The 3 patients had received doses among the high est studied, and the toxicity appeared to be dose related and cumulati ve. The evidence suggests that higher doses generated higher C(max) an d AUC values, which may be correlated with toxic effects.