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Pediatric phase I trial and pharmacokinetic study of tiazofurin (NSC 286193)
Insights
Tiazofurin, a nucleoside antimetabolite, showed promise in a Phase I trial for pediatric refractory cancers. The maximally tolerated dose was 2200 mg/sq m/day, with neurotoxicity being the primary dose-limiting factor.
Area of Science:
- Oncology
- Pharmacology
- Pediatric Medicine
Background:
- Tiazofurin is a novel nucleoside antimetabolite with potential anticancer activity.
- Pediatric refractory cancers represent a significant unmet medical need, necessitating novel therapeutic approaches.
Purpose of the Study:
- To evaluate the safety, tolerability, and pharmacokinetics of tiazofurin in children with refractory cancers.
- To determine the maximally tolerated dose (MTD) of tiazofurin in this patient population.
Main Methods:
- A Phase I clinical trial was conducted administering intravenous tiazofurin daily for 5 consecutive days every 3 weeks.
- Doses ranged from 550 to 3300 mg/sq m/day, with toxicity and pharmacokinetic assessments performed.
- Seventeen patients received 23 courses of treatment.
Main Results:
- The MTD of tiazofurin was determined to be 2200 mg/sq m/day.
- The primary dose-limiting toxicities were nonhematological, predominantly neurotoxicity (headache, drowsiness, irritability) and severe myalgias.
- Mild, reversible elevations in transaminases, gastrointestinal upset, hypertension, dysphagia, and dermatitis were also observed. Myelotoxicity was not significant.
- Pharmacokinetic analysis revealed triphasic plasma disappearance with half-lives of 9.7 min, 1.6 h, and 5.5 h. Renal excretion was the primary elimination route.
Conclusions:
- Tiazofurin can be administered safely to children with refractory cancers up to a dose of 2200 mg/sq m/day.
- Neurotoxicity is a key dose-limiting toxicity that requires careful monitoring.
- Further investigation into the efficacy of tiazofurin in pediatric malignancies is warranted.
Abstract:
Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide), a new nucleoside antimetabolite, was evaluated in a phase I trial involving children with refractory cancers. The drug was administered i.v. as 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 of elimination was renal with 85% of the drug recoverable in the urine as the parent compound in the 24 h following administration.