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Phase I and Clinical Pharmacology Study of Intravenous Flavone Acetic Acid (NSC 347512)¹

Section of Medical Oncology, Department of Medicine, Walter Reed Army Medical Center, Washington, DC 20307 [R. B. W., R. D. K., J. J. P.]; Division of Cancer Treatment, National Cancer Institute, Bethesda, 20892 [R. F. G., J. M. C., A. S., G. A. C.]; and Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814 [R. B. W., R. D. K.]

We have conducted a Phase I and pharmacological study of flavone acetic acid, one of a series of novel flavonoids. The drug was administered i.v. weekly for 4 weeks, with a 2-week rest and then repeated. Flavone acetic acid was given initially in a 1-h infusion, but at the 3900-mg/m² dose level, the infusion time was lengthened to 3 h. A total of 31 patients were treated with 9 different dose levels, ranging from 330 to 6400 mg/m². Dose-limiting toxicity was acute hypotension that began after about one-third of each drug dose had been infused and rarely lasted more than a few minutes after the infusion was discontinued. In addition, subjective fatigue and asthenia causing unacceptable patient discomfort was dose limiting. A significant side effect noted that was not dose limiting was diarrhea during the infusion. This drug exhibited nonlinear pharmacokinetic behavior. Plasma levels exceeded 300 µg/ml during the infusion at the maximally tolerated dose. After the infusion ended the principal half-life was about 2 h. In 24-h urine collections 27% of the flavone acetic acid dose was recovered as intact drug and an additional 37% was recovered as a metabolite. The maximally tolerated dose determined in this study is 6400 mg/m² given i.v. over 3 h.

¹ Presented in part at the American Society of Clinical Oncology meeting in Atlanta, GA, May 17–19, 1987. The opinions expressed in this article are solely those of the authors and do not necessarily reflect those of any United States Government agency.

² To whom requests for reprints should be addressed, at Section of Medical Oncology, Walter Reed Army Medical Center, Washington, DC 20307.

Received 2/ 2/88. Revised 6/17/88. Accepted 7/19/88.

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