Zalcitabine.
OBJECTIVE
To review the chemistry, intracellular metabolism, pharmacokinetics, and clinical trials of zalcitabine (2'3'-dideoxycytidine, ddC).


METHODS
English-language articles and conference procedings. The indexing terms used were zalcitabine, 2'3'-dideoxycytidine, and ddC.


METHODS
In addition to the manufacturer's package insert, available Phase I and Phase I/II studies were reviewed.


METHODS
Clinical experience with ddC has been limited to uncontrolled studies and an expanded-access program. Efficacy was evaluated solely on surrogate markers of HIV disease: CD4+ lymphocyte counts and p24 antigen determinations. Clinical endpoints, such as disease progression and survival rates, must be provided to the Food and Drug Administration (FDA) for continued approval.


RESULTS
The FDA has approved use of ddC in combination with zidovudine (ZDV) as therapy of HIV infection for patients with CD4+ lymphocyte counts < or = 300 cells/mm3 who have experienced significant clinical or immunologic deterioration. Although ddC has the same mechanism of action as other nucleoside analogs, it is more potent on a molar basis. The drug is stable in gastric pH and has good bioavailability (approximately 70-90 percent), but is rapidly cleared from plasma (half life approximately 1-3 h). Intracellular concentrations of ddC triphosphate, the active form, are probably related to plasma concentrations, yet may persist in cells longer than the parent drug persists in plasma. When used as primary therapy in patients with CD4+ < or = 300 cells/mm3, ddC/ZDV increased CD4+ lymphocyte counts and reduced plasma p24 antigen concentrations. In comparison to ZDV monotherapy data taken from other studies, ddC/ZDV appeared to demonstrate a more pronounced and sustained increase in CD4+ cell counts; however, this observation cannot be confirmed until the results of ZDV-controlled comparisons are available. Overall, 17-31 percent of the patients receiving the currently recommended initial dosage of ddC experience peripheral neuropathy.


CONCLUSIONS
In combination with ZDV, ddC appears to augment the CD4+ cell response of ZDV monotherapy in the treatment of HIV infection for ZDV-naive patients, although controlled studies and rigorous statistical analyses are lacking at present. The efficacy of ddC/ZDV in patients who received prior treatment with ZDV monotherapy is unclear at the present.
Shelton
M J
MJ
American Foundation for AIDS Research, Center for Clinical Pharmacy Research, Buffalo, NY.
O'Donnell
A M
AM
Morse
G D
GD
D000293:Adolescent; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007223:Infant; D016047:Zalcitabine / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D015215:Zidovudine / Q000627:therapeutic use
D015215:Zidovudine; D016047:Zalcitabine