Abstract
One of a novel series of compounds (AMAPS or arylmethylaminopropanediols), 773U82-HCl has shown significant antitumor activity inin vitro and inin vivo tumor systems, but has less animal CNS toxicity than the lead compound in the same series (crisnatol). This study was designed to evaluate the pharmacokinetics, qualitative and quantitative toxicities of 773U82-HCl and to determine the recommended phase II dose (MTD) of 773U82-HCl given as a short infusion daily for 3 days every 3 weeks. Twenty-nine patients with refractory malignancies received 79 courses over 9 dose levels during this study. Doses ranged from 50 to 1060 mg/m2d×3 days. Due to the possibility of local hemolysis with concentrations > 1.5 mg/ml, drug was administered in solutions containing ≤ 1.5 mg/ml. Because large volumes were needed at the higher dose levels, the infusion duration was increased from 2 hours to 4 hours. Mild to moderate nausea, vomiting, fatigue, dizziness and headaches were observed. Myelosuppression was the dose limiting toxicity. The recommended phase II dose and schedule was determined to be 800 mg/m2d×3d every 3 weeks. 773U82-HCl plasma concentration-time data were analyzed using a two-compartment pharmacokinetic model. The t1/2β averaged 6 hours and the total body clearance was 75.9 L/hr/m2. The volume of distribution (Vdss) was large, averaging 470 L/m2.
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Abbreviations
- ECG:
-
electrocardiogram
- t1/2 :
-
half-life
- Vdss:
-
volume of distribution
- HPLC:
-
highperformance liquid chromatography
- Vdss :
-
steady-state volume of distribution
- AUC:
-
area under the concentration × time curve
- CL:
-
total body clearance
- Cmax :
-
peak plasma level
- Vc :
-
central volume of distribution
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Bailey, H., Kohler, P., Tuttle, R. et al. Phase I evaluation of 773U82-HCl in a two-hour infusion repeated daily for three days. Invest New Drugs 10, 279–287 (1992). https://doi.org/10.1007/BF00944182
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DOI: https://doi.org/10.1007/BF00944182