Brands, Medical Use, Clinical Data
- Anti-HIV Agents
- Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
Brands / Synonyms
Ddc; Ddcyd; Dideoxycytidine; Hivid; HIVID
For the treatment of Human immunovirus (HIV) infections.
Zalcitabine inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.
Mechanism of Action
Zalcitabine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Zalcitabine is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated.
Biotrnasformation / Drug Metabolism
HIVID is contraindicated in patients with clinically significant hypersensitivity to zalcitabine or
to any of the excipients contained in the tablets.
Zidovudine: There is no significant pharmacokinetic interaction between ZDV and
zalcitabine which has been confirmed clinically. Zalcitabine also has no significant effect on the intracellular
phosphorylation of ZDV, as shown in vitro in peripheral blood mononuclear cells or in two other cell lines (U937 and
Molt-4). In the same study it was shown that didanosine and stavudine had no significant effect on the intracellular
phosphorylation of zalcitabine in peripheral blood mononuclear cells.
Lamivudine: In vitro studies in peripheral blood mononuclear cells, U937 and Molt-4
cells revealed that lamivudine significantly inhibited zalcitabine phosphorylation in a dose dependent manner.
Effects were already seen with doses corresponding to relevant plasma levels in humans, and the intracellular
phosphorylation of zalcitabine to its three metabolites (including the active zalcitabine triphosphate metabolite)
was significantly inhibited. Zalcitabine inhibited lamivudine phosphorylation at high concentration ratios (10 and
100); however, it is considered to be unlikely that this decrease of phosphorylated lamivudine concentration is of
clinical significance, as lamivudine is a more efficient substrate for deoxycytidine kinase than zalcitabine. These
in vitro studies suggest that concomitant administration of zalcitabine and lamivudine in humans may result in
sub-therapeutic concentrations of active phosphorylated zalcitabine, which may lead to a decreased antiretroviral
effect of zalcitabine. It is unknown how the effect seen in these in vitro studies translates into clinical
consequences. Concomitant use of zalcitabine and lamivudine is not recommended.
Saquinavir: The combination of HIVID, saquinavir, and ZDV has been studied (as triple
combination) in adults. Pharmacokinetic data suggest that absorption, metabolism, and elimination of each of these
drugs are unchanged when they are used together.
Drugs Associated With Peripheral Neuropathy: The concomitant use of HIVID with drugs
that have the potential to cause peripheral neuropathy should be avoided where possible. Drugs that have been
associated with peripheral neuropathy include antiretroviral nucleoside analogues, chloramphenicol, cisplatin,
dapsone, disulfiram, ethionamide, glutethimide, gold, hydralazine, iodoquinol, isoniazid, metronidazole,
nitrofurantoin, phenytoin, ribavirin, and vincristine. Concomitant use of HIVID with didanosine is not
Intravenous Pentamidine: Treatment with HIVID should be interrupted when the use of a
drug that has the potential to cause pancreatitis is required. Death due to fulminant pancreatitis possibly related
to intravenous pentamidine and HIVID has been reported. If intravenous pentamidine is required to treat
Pneumocystis carinii pneumonia, treatment with HIVID should be interrupted.
Amphotericin, Foscarnet, and Aminoglycosides: Drugs such as amphotericin, foscarnet,
and aminoglycosides may increase the risk of developing peripheral neuropathy or other HIVID-associated adverse
events by interfering with the renal clearance of zalcitabine (thereby raising systemic exposure). Patients who
require the use of one of these drugs with HIVID should have frequent clinical and laboratory monitoring with dosage
adjustment for any significant change in renal function.
Probenecid or Cimetidine: Concomitant administration of probenecid or cimetidine
decreases the elimination of zalcitabine, most likely by inhibition of renal tubular secretion of zalcitabine.
Patients receiving these drugs in combination with zalcitabine should be monitored for signs of toxicity and the dose
of zalcitabine reduced if warranted.
Magnesium/Aluminum-containing Antacid Products: Absorption of zalcitabine is moderately
reduced (approximately 25%) when coadministered with magnesium/aluminum-containing antacid products. The clinical
significance of this reduction is not known, hence zalcitabine is not recommended to be ingested simultaneously with
Metoclopramide: Bioavailability is mildly reduced (approximately 10%) when zalcitabine
and metoclopramide are coadministered.
Doxorubicin: Doxorubicin caused a decrease in zalcitabine phosphorylation (>50%
inhibition of total phosphate formation) in U937/Molt 4 cells. Although there may be decreased zalcitabine activity
because of lessened active metabolite formation, the clinical relevance of these in vitro results are not known.