A multi-institutional study may offer clues for the treatment of some autoimmun...( at M.D. Anderson Cleveland Clinic Foun...)

at M.D. Anderson, Cleveland Clinic Foundation, University of Florida/Shands Hospital, University of Alabama at Birmingham, Mt. Sinai Hospital, Cornell/New York. Hospital, Tufts-New England Medical Center, and Duke University Medical Center. The authors will present their findings at the American Physiological Society's (APS) (www.the-aps.org) annual scientific conference, Experimental Biology 2003, being held April 17-21, 2004, at the Washington, D.C. Convention Center.

Methodology

This was a Phase I study, the first step in human testing of a new drug. These trials evaluate drug safety and toxicity at different dose levels in a small number of volunteers. This study consisted of intravenous five-day, twice daily dosing cycles, separated by two to four weeks in patients with cancer. The Phase I pharmacokinetic study (the movement of drugs throughout the body) consisted of a single oral dose after four to eight days of a single IV dose. This was followed by two days of IV dosing twice a day.

This investigation included a determination of drug pharmacokinetics and several markers related to drug activity or pharmacodynamics. These markers included plasma dGuo and inosine, erythrocyte PNP activity, and intracellular dGTP. BCX-1777, dGuo, and inosine were determined by high performance liquid chromatography coupled with mass spectrometry detection. PNP activity was monitored by enzymatic assay and cellular dGTP was determined by DNA polymerase assay.

Results

Intravenous IV administration of 10, 26, 40, 60, or 90 mg/m² BCX-1777 to cancer patients results in a rapid elevation of plasma dGuo, going from ≤0.004 μM prior to dosing to 2.4—34 μM after dosing. In contrast, in normal rats, dogs, and primates the dGuo range was smaller (1.5-4.5 μM). The range of BCX-1777-dependent dGuo responses in cancer patients may be related to differences in the d
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Contact: Donna Krupa
djkrupa1@aol.com
703-527-7357
American Physiological Society
19-Apr-2004

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