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Zalcitabine is a dideoxynucleoside antiretroviral agent that is phosphorylated to the active metabolite 2′,3′-dideoxycytidine 5′-triphosphate (ddCTP) within both uninfected and HIV-infected cells. At therapeutic concentrations, ddCTP inhibits HIV replication by inhibiting the enzynie reverse transcriptase and terminating elongation of the proviral DNA chain.
The results of 3 large pivotal trials comparing zidovudine monotherapy with combination therapy have now clearly established that zalcitabine plus zidovudine combination therapy improves survival, delays disease progression and is associated with an improvement in viral load and CD4+ cell count compared with zidovudine monotherapy. More recently, clinical end-point and surrogate marker data have established the efficacy of zalcitabine in combination with the protease inhibitor saquinavir in zidovudine-experienced patients. Other studies have demonstrated the utility of zalcitabine in combination with ritonavir and the nucleoside analogue lamivudine. Importantly, early use of zalcitabine in the treatment sequence does not appear to limit the therapeutic efficacy of subsequent therapy with other nucleoside analogues such as lamivudine.
Peripheral neuropathy is the most frequent dose-limiting adverse effect associated with zalcitabine therapy and is generally reversible on discontinuation of treatment. Stomatitis and mouth ulcers may occur frequently with zalcitabine therapy but tend to resolve with continuing treatment. Haematological toxicity, which is a common adverse effect associated with zidovudine, is reported infrequently with zalcitabine. Overall, combination therapy with zalcitabine plus zidovudine or saquinavir has been shown to have a tolerability profile comparable to that of either agent alone, although treatment with zidovudine plus zalcitabine was associated with a significant increase in the incidence of haematological toxicity compared with zidovudine monotherapy in one study.
Therefore, current data suggest that zalcitabine is a useful antiretroviral agent for inclusion as a component of initial double combination therapy with zidovudine or as part of triple combination therapy including zidovudine plus a protease inhibitor in the management of patients with HIV infection.
Zalcitabine is phosphorylated to the active antiviral compound 2′,3′-dideoxy-cytidine 5′-triphosphate (ddCTP) within both uninfected and HIV-infected cells. ddCTP inhibits HIV replication by inhibition of the enzyme reverse transcriptase and termination of viral DNA chain elongation. In both these roles ddCTP competes with endogenous deoxycytidine triphosphate. Zalcitabine has demonstrated significant antiretroviral activity against HIV-1 in vitro. In addition, synergistic antiretroviral activity has been reported for zalcitabine in combination with several other antiretroviral agents including zidovudine, stavudine and saquinavir.
Resistance to zalcitabine usually arises from a series of mutations within the HIV pol gene and develops less frequently than resistance to zidovudine. Cross-resistance between zidovudine and zalcitabine has been described. The activation state of the target cell, whether the cell under investigation is acutely or chronically infected with HIV, and/or the levels of intracellular phosphorylating enzymes may also contribute to variation in the antiviral activity of zalcitabine between cell lines.
In vitro investigations suggest that zalcitabine-induced inhibition of an enzyme responsible for the synthesis of mitochondrial DNA (DNA polymerase γ) may be responsible for the development of peripheral neuropathy in clinical practice.
Following oral administration, zalcitabine is rapidly absorbed, with peak plasma concentrations typically achieved in 1 to 2 hours. The oral bioavailability of zalcitabine exceeded 80% in some studies. Zalcitabine partially crosses the blood-brain barrier; drug concentrations in the CSF represented a mean of 14 to 20% of simultaneously measured plasma concentrations. Placental transfer of zalcitabine has been reported in vitro and in vivo.
Zalcitabine has a short plasma elimination half-life of 1.1 to 1.8 hours and is predominantly excreted unchanged in the urine. Hepatic metabolism of the drug is minimal and only about 10% of an orally administered dose is excreted in the faeces.
The results of 3 large pivotal studies, ACTG 175, CPCRA 007 and Delta, have clearly demonstrated that combination therapy with zidovudine plus zalcitabine or zidovudine plus didanosine improves survival and delays disease progression compared with zidovudine monotherapy. Although not exclusively limited to zidovudine-naive patients, the benefits of zalcitabine plus zidovudine therapy appear to be greater in this patient population than in zidovudine-experienced patients. Improvements in surrogate marker and clinical end-points have also been reported in zidovudine-experienced patient populations with advanced HIV infection (CD4+ cell count 50 to 300 cells/μl) treated with 2- or 3-drug combination regimens comprising zalcitabine plus the protease inhibitor saquinavir ± zidovudine. Zalcitabine has also demonstrated utility in combination with the protease inhibitor ritonavir as first-line treatment in a pilot study. Impressive surrogate marker data have also been reported in zidovudine-experienced patients receiving a 3-drug regimen comprising lamivudine, zalcitabine and zidovudine. Furthermore, the addition of lamivudine ± loviride to ongoing therapy with zidovudine plus zalcitabine in patients with advanced HIV infection was associated with a greater reduction in disease progression compared with the addition of lamivudine ± loviride to zidovudine alone. This therefore suggests that prior use of zalcitabine does not limit the subsequent utility of other nucleoside analogues such as lamivudine.
Peripheral neuropathy is the major dose-limiting adverse effect associated with zalcitabine therapy and has been reported to occur in 12 to 46% of patients in clinical studies; risk factors for the development of zalcitabine-induced peripheral neuropathy include a baseline CD4+ count ≤50 cells/μl, diabetes mellitus and a low serum cobalamin level. Mouth ulcers and stomatitis occurred with an incidence of 3 to 4% in 3 large studies and 29% in a fourth study; these effects may resolve with continuing administration of the drug. Pancreatitis is an infrequent adverse effect associated with zalcitabine therapy, generally developing in <1% of patients. Other adverse effects associated with zalcitabine include hepatotoxicity and cutaneous/hypersensitivity reactions.
The tolerability profile of combination therapy with zalcitabine plus zidovudine or saquinavir generally reflects that of the individual drugs and has not been associated with the development of any unexpected adverse effects. However, the incidence of haematological adverse effects with zidovudine plus zalcitabine therapy was significantly greater than that reported for zidovudine alone in one study.
Although tolerability data in children are limited, rash, stomatitis and peripheral neuropathy have been reported after administration of the drug to this patient group.
Several important drug interactions have been reported between zalcitabine and other drugs used in the management of patients with HIV infection. Potentially nephrotoxic agents, notably the aminoglycosides, amphotericin and foscarnet, may reduce the renal clearance of zalcitabine and potentially increase the incidence of zalcitabine-associated adverse effects. Importantly, the concomitant use of zalcitabine with pentamidine should be avoided because of an increased risk of the development of severe pancreatitis. Furthermore, zalcitabine should be coadministered with caution with other drugs that may cause peripheral neuropathy (for example, didanosine, dapsone, metronidazole, stavudine, isoniazid and pentamidine) should be avoided where possible. A reduction in the bioavailability of zalcitabine has been reported with the concomitant administration of aluminium hydroxide/magnesium hydroxide antacid mixture.
To date, clinically significant pharmacokinetic interactions have not been reported between zalcitabine and other antiretroviral agents including zidovudine, saquinavir and nevirapine. However, inhibition of zalcitabine phosphorylation by lamivudine has been reported in vitro.
Dosage and Administration
The recommended dosage of zalcitabine for use in combination with zidovudine in adults and adolescents (age >13 years) is 0.75mg administered orally every 8 hours. The same dosage is recommended for use in combination with the protease inhibitor saquinavir. The optimal dosage of zalcitabine as part of triple combination therapy has yet to be determined, although 0.75mg every 8 hours has been widely used in clinical studies.
Zalcitabine dosage should be reduced in patients with renal insufficiency; 0.75mg twice daily is recommended in patients with a creatinine clearance (CLCR) of 0.6 to 2.4 L/h (10 to 40 ml/min) decreasing to 0.75mg once daily in patients with a CLCR<0.6 L/h (<10 ml/min). Zalcitabine should be discontinued if peripheral neuropathy develops and reinstituted (at a dose of 0.375mg every 8 hours) only if symptoms become no more than mild in nature. Caution is also recommended when the drug is administered to patients with a history of poor bone marrow reserve, elevated amylase levels, pancreatitis or alcohol abuse and in patients receiving parenteral nutrition.
KeywordsZidovudine Didanosine Zalcitabine Triple Combination Therapy Human Immuno Deficiency Virus Type
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