PEDIATRIC PHASE-I TRIAL AND PHARMACOKINETIC STUDY OF TIAZOFURIN (NSC 286193)

  • 1 January 1985
    • journal article
    • research article
    • Vol. 45  (10) , 5169-5172
Abstract
Tiazofurin (2-.beta.-D-ribofuranosylthiazole-4-carboxamide), a new nucleoside antimetabolite, was evaluated in a phase 1 trial involving children with refractory cancers. The drug was administered i.v. was a 10-min infusion daily for 5 consecutive days repeated at 3-week intervals. The dose ranged from 550 to 3300 mg/sq m/day. Seventeen patients received 23 courses and were evaluable for toxicity. The maximally tolerated dose was 2200 mg/sq m/day. The major dose-limiting toxicities were nonhematological. Neurotoxicity, including headache, drowsiness, and irritability, was common and was the principal dose limiting toxicity at the higher doses. Severe myalgias were also dose limiting in one patient. Other side effects were mild, reversible elevations in serum transaminases; nausea, vomiting, and diarrhea; mild hypertension; dysphagia; and exfoliative dermatitis of the hands and feet. Myelotoxicity was not significant. The pharmacokinetics of tiazofurin was studied in 16 patients. Plasma disappearance was triphasic with half-lives of 9.7 min, 1.6 h, and 5.5 h. Clearance was dose related, ranging from 120 ml/min/sq m at 550 mg/sq m/day to 70 ml/min/sq m at 3300 mg/sq m/day. The primary route in elimination was renal with 85% of the drug recoverable in the urine as the parent compound in the 24 h following administration.

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