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Zalcitabine

A Review of its Pharmacology and Clinical Potential in Acquired Immunodeficiency Syndrome (AIDS)

  • Drug Evaluation
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Summary

Synopsis

Zalcitabine is an analogue of the nucleoside deoxycytidine which, when intracellularly converted to an active triphosphate metabolite, inhibits replication of human immunodeficiency virus (HIV). Zalcitabine is thought to act in the early phase of HIV replication by inhibiting reverse transcriptase and terminating the viral DNA chain. In vitro, zalcitabine is one of the more effective nucleoside analogues currently in clinical use for HIV infection, with 0.5 μmol/L concentrations completely inhibiting HIV replication in human T lymphocyte cell lines. In clinical trials, p24 antigen levels decreased and CD4 cell counts increased in patients with acquired immunodeficiency syndrome (AIDS) receiving zalcitabine 0.03 mg/kg/day as monotherapy. Dose-dependent adverse effects that include peripheral neuropathy, stomatitis and rash, restrict long term use at higher dosages, and it is unclear whether zalcitabine monotherapy is as effective as zidovudine in extending survival in HIV-infected patients. Alternating or concomitant therapy with zalcitabine and zidovudine provides effective inhibition of viral replication and disease progression (as measured by improvements in CD4 cell counts) with lower and less toxic dosage regimens. At present, therefore, zalcitabine has a place in AIDS therapy both in combination with zidovudine, and as monotherapy for patients unable to tolerate zidovudine.

Pharmacodynamic Properties

Zalcitabine (2′,3′-dideoxycytidine, ddC) is a pyrimidine analogue, that when phosphorylated intracellularly to the active triphosphate metabolite, inhibits the cytopathic effects evinced by human immunodeficiency virus (HIV). Zalcitabine has been demonstrated by some in vitro assay methods to be among the most effective nucleoside analogues in current clinical use, completely inhibiting HIV replication in human T lymphocyte cell lines at 0.5 μmol/L concentrations. In vitro effects of zalcitabine vary in different cell cultures, as endogenous deoxycytidine triphosphate competes for reverse transcriptase active sites, and levels of cytokines may modulate the antiviral activity. Zalcitabine has shown synergistic antiviral activity in vitro when combined with either recombinant interferon alpha A, soluble CD4, dextran sulphate or dipyridamole, and an additive to synergistic effect when combined with zidovudine.

Pharmacokinetic Properties

Zalcitabine exhibits linear pharmacokinetic behaviour at clinically relevant concentrations. Pharmacokinetic parameters are not influenced by route of administration (intravenous or oral), although the absorption rate of zalcitabine is decreased by food. Peak plasma concentrations of 0.45 to 1.5 /Limol/L occur 1 to 2 hours after oral administration of zalcitabine 0.25 mg/kg to adults, with bioavailability approximating 88%. Zalcitabine is less able to cross the blood-brain barrier than zidovudine, with cerebrospinal fluid drug concentrations being 14 to 20% of simultaneously obtained plasma zalcitabine concentrations. The majority (75%) of the drug is excreted unchanged in the urine.

Clinical Efficacy

A variety of disease markers are used to evaluate drug efficacy in HIV-infected patients. The most commonly reported, but conceivably not the most reliable of these markers, are p24 anti-genaemia and counts of cells expressing the CD4 cell surface receptor (CD4 cells). In patients with AIDS or AIDS-related complex (ARC) receiving zalcitabine monotherapy, a dose-dependent reduction in serum p24 antigen levels was observed within the first 3 weeks of therapy. Increases in CD4 cell counts were noted later in therapy, and were more likely in patients receiving dosages of 0.08 mg/kg/day or more, with maximum levels obtained after 8 to 12 weeks of therapy reported in one trial. Patients who tolerated zalcitabine gained weight and reported decreased feelings of fatigue. Results were similar in children. In most of the trials reported, however, large numbers of patients withdrew due to an inability to tolerate the adverse effects associated with zalcitabine therapy. Zalcitabine monotherapy may be less effective than zidovudine in improving survival of patients.

Alternating and concomitant therapy with zalcitabine and zidovudine appeared to improve the tolerability of both drugs. In 1 trial in patients with AIDS or ARC treated with zalcitabine 0.015 to 0.03 mg/kg/day given concomitantly with zidovudine 150 to 600 mg/day, sustained decreases in p24 antigenaemia were observed during 1 year of therapy, and CD4 cell counts improved dose-dependently.

Clinical Tolerability

Adverse events associated with zalcitabine therapy are very common, with the predominant effects including peripheral neuropathy in the feet and legs, stomatitis and rash. Pancreatitis is a serious but rare complication, affecting < 1% of patients receiving zalcitabine as monotherapy. Neuropathy and rash symptoms have a dose-dependent relation to zalcitabine administration, with onset delayed and severity decreased in patients receiving dosage regimens ⩽ 0.03 mg/kg/ day. Neurological symptoms are more common in patients who have pre-existing neuropathy. A period of intensified neuropathy (’coasting’) often follows cessation of zalcitabine therapy, with most patients who have received dosages < 0.01 mg/kg/day recovering completely after 6 months. Unlike zidovudine, haematological toxicity is rare in patients receiving zalcitabine.

Dosage and Administration

Zalcitabine has been administered as intravenous and oral preparations, with dosages ranging from 0.15 to 0.75 mg/kg/day in divided dosages 4-to 8-hourly. As monotherapy, 0.03 mg/kg/ day appears to be tolerable for both adults and children. Combination therapy dosages range from 0.015 to 0.03 mg/kg/day, with zidovudine given at dosages of 150 to 600 mg/day. Zalcitabine is inadvisable for patients with pre-existing neuropathy or nephropathy.

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Various sections of the manuscript reviewed by: J.C.C. Borleffs, Department of Internal Medicine, Immunology and Infection, Academisch Ziekenhuis Utrecht, Utrecht, The Netherlands; N. Clumeck, Université Libre de Bruxelles, Saint Pierre Hospital, Brussels, Belgium; E. De Clercq, Katholieke Universiteit Leuven, Rega Institute, Leuven, Belgium; M.D. de Jong, National AIDS Therapy Evaluation Centre, Amsterdam, The Netherlands; B.G. Gazzard, Westminster Hospital, London, England; M. Magnani, Universita’ degli Studi di Urbino, Istituto di Chimica Biologica Giorgio Fornaini, Urbino, Italy; A.J. Pinching, Medical College of Saint Bartholomew’s Hospital, University of London, England; W. Powderly, AIDS Clinical Trials Unit, Washington University School of Medicine, St Louis, Missouri, USA; D.D. Richman, Departments of Pathology and Medicine, University of California San Diego, La Jolla, California, USA; G. Skowron, Roger Williams Medical Center, Department of Medicine, Division of Infectious Diseases, Providence, Rhode Island, USA.

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Whittington, R., Brogden, R.N. Zalcitabine. Drugs 44, 656–683 (1992). https://doi.org/10.2165/00003495-199244040-00009

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