Phase I and pharmacokinetic study of tiazofurin (TCAR,NSC 286193) administered by continuous infusion |
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Authors: | Gerald Batist Raymond W Klecker Jr Hiremagalur N Jayaram Jean F Jenkins John Grygiel Daniel C Ihde Joyce L Eddy Robert L Fine Ian G Kerr Jerry M Collins |
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Institution: | (1) Clinical Pharmacology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda;(2) NCI-Navy Branches, Clinical Oncology Program, Division of Cancer Treatment, National Cancer Institute, Bethesda;(3) Laboratory of Medicinal Chemistry and Pharmacology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda;(4) Clinical Pharmacology Branch, National Cancer Institute, Building 10, Room 6N119, 20205 Bethesda, MD, USA |
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Abstract: | Summary Tiazofurin (2--D-ribofuranosylthiazole-4-carboxamide, TCAR) is a synthetic C-nucleoside that demonstrated significant in vivo activity against a variety of animal tumors as well as in vitro activity against human tumor-derived cell lines. Thirteen patients were treated with TCAR administered as a 5-day continuous infusion in this Phase I trial. Seventeen complete cycles were administered in three dose levels ranging from 550 to 1450 mg/M2. Dose-limiting toxicities were myelosuppression and neurotoxicity including severe lethargy. Other toxicities including superficial skin peeling, myalgias, and tearing were seen at all doses. One patient had chest pain on day 4 resulting in stopping the drug, however, there was no evidence of cardiac or pericardial disease. Uric acid levels rose within one day in the absence of allopurinol treatment. There were no treatment related deaths. HPLC measurement of drug levels demonstrated steady-state plasma levels during the infusion, and a half-life following the infusion of 7.7 ± 0.6 hours. Minor abnormalities in renal function were associated with dramatic changes in pharmacokinetics and toxicity. No clinical responses were observed in this trial.Abbreviations TCAR
Tiazofurin
- HPLC
High performance liquid chromatography
- IMPD
Inosine monophosphate dehydrogenase
- WBC
white blood cell
- CPK
creatine phosphokinase
- Css
steady-state concentration |
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