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Phase I and Clinical Pharmacology Trial of 502U83 Using a Monthly Single Dose Schedule¹

Division of Oncology, Department of Medicine and School of Pharmacy, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284-7884 [D. D. V. H., J. G. K., K. A. H., T. D. B., G. R. W., J. N. T., J. M. K., G. L. F.], and Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709 [J. P., A-M. L., V. S. L., K. W. B., W. W., J. H., R. L. T.]

502U83 is an arylmethylaminopropanediol derivative exhibiting significant antineoplastic activity in a number of murine and human tumor models. In this Phase I trial, a 1-h or 4-h infusion of the agent was administered i.v. in 250 ml of 5% dextrose in water every 28 days. Fifty-three courses at doses of 25 to 2000 mg/m² were administered to 36 patients with refractory solid tumors. Prolongation of the PR, QRS, and QT intervals on electrocardiograms was dose limiting at 2000 mg/m². This prolongation appeared dose related and was reversible upon discontinuation of the infusion. No hematological toxicity was observed. Other toxicities included only sporadic and mild to moderate nausea and vomiting. No tumor responses were noted.

502U83 plasma concentrations were determined by high-pressure liquid chromatography. Complete pharmacokinetic profiles were obtained for 21 of the 36 patients. After infusion, plasma concentrations declined in a biexponential or in a triexponential manner with a harmonic mean terminal t of 8.83 h. Using a three-compartment model, the mean apparent volume of distribution at steady state and total-body clearance were 195 liters/m² and 42.5 liters/h/m², respectively, indicative of extensive tissue distribution. No correlation could be found between the pharmacokinetic parameters and prolongation of the cardiac conduction intervals. Because of the cardiac effects with the drug, the schedule of administration of 502U83 used in this study cannot be recommended.

¹ Supported by NIH Grant RR-01346, a grant from Burroughs Wellcome Co., a grant from the American Cancer Society (Clinical Oncology Career Development Award to G. R. W.), and the clinical and support services of Audie L. Murphy Memorial Veterans Administration Hospital, San Antonio, TX. G. L. F. is an established Investigator of the American Heart Association.

² To whom requests for reprints should be addressed, at Section of Drug Development, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7884.

Received 1/ 9/90. Accepted 8/30/90.