For definition of Groups, see Preamble Evaluation.
VOL.: 76 (2000) (p. 129)
CAS No.:
Chem. Abstr. Name: 2¢,3¢-Dideoxycytidine
5.1 Exposure data
Zalcitabine is a nucleoside analogue that has been used to treat HIV infections in adults and children. The drug entered clinical use around 1990, but it is no longer in common use since several clinical studies showed it to be less active than other nucleoside analogues.
5.2 Human carcinogenicity data
The only data available were from two trials designed to assess the efficacy of zalcitabine in improving the degree of immunocompetence and survival of patients with HIV infection and one phase I trial of zalcitabine alternated with zidovudine. No conclusion could be drawn concerning carcinogenicity.
5.3 Animal carcinogenicity data
Zalcitabine was tested for carcinogenicity in four studies in mice by gavage. Treatment resulted in induction of thymic lymphomas in all studies.
5.4 Other relevant data
The human pharmacokinetics of orally administered zalcitabine appears to be linear over a broad dose range. Zalcitabine is about 80% bioavailable and is rapidly absorbed, distributed and eliminated in urine, mainly as the unchanged drug. Phosphorylation is essential to its antiviral activity but accounts for a very small fraction of its total disposition. Its pharmacokinetics in several species of experimental animals are similar to that in humans.
Side-effects observed in clinical trials and use include peripheral neuropathy, mucositis and, rarely, hepatotoxicity. Several of these effects, particularly neurotoxicity and hepatotoxicity, also occur in non-human primates, dogs, rabbits and rodents treated with zalcitabine.
No studies were available on the reproductive or prenatal effects of zalcitabine in humans. Developmental toxicity, with effects on litter size and fetal weight and malformations, was observed after oral administration of 1000 mg/kg bw per day zalcitabine to mice on days 6–15 of gestation. Studies of transplacental pharmacokinetics in monkeys indicated that zalcitabine crosses the placenta by passive diffusion; zalcitabine and zalcitabine monophosphate appear in fetal plasma and tissues after administration of zalcitabine to pregnant animals.
The limited data on genetic and related effects indicate that zalcitabine is primarily a clastogenic agent at high concentrations, consistent with its action as a DNA chain terminator.
5.5 Evaluation
There is inadequate evidence in humans for the carcinogenicity of zalcitabine.
There is sufficient evidence in experimental animals for the carcinogenicity of zalcitabine.
Overall evaluation
Zalcitabine is possibly carcinogenic to humans (Group 2B).
For definition of the italicized terms, see Preamble Evaluation.
Synonyms
See Also:
Toxicological Abbreviations