STRUCTURE

Zalcitabine is derived from cytidine (similar to lamivudine) and lacks the 3′-OH moiety on the ribose sugar (Fig. 7-1). Zalcitabine shares its nucleotide base with lamivudine, but they differ in their sugar moieties and stereochemistry. To become active as an antiretroviral agent, zalcitabine must undergo triphosphorylation to the 5′-triphosphate form.

Figure 7-1 Biochemical structure of zalcitabine.

MECHANISMS OF ACTION AND IN VITRO ACTIVITY

Zalcitabine acts as an inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and as a chain terminator.² It inhibits HIV-1 replication and protects against cytopathogenicity at concentrations of 0.5 μM.²^–⁴ Zalcitabine is active against HIV-1 in a variety of cell lines, including peripheral blood lymphocytes and those derived from lymphocytes or monocyte/macrophages, although its inhibitory activity and metabolism may be different across cell lines.⁴ Zalcitabine is especially active against macrophage-tropic strains in monocyte/macrophage cell lines, with a median inhibitory concentration (IC₅₀) of 0.002 μM, compared to 0.01 μM for didanosine and 0.20 μM for zidovudine.⁵ Zalcitabine is active against zidovudine-resistant HIV-1 isolates,⁶^–⁸ HIV-2,⁹ and hepatitis B virus^10,¹¹ but not against herpes simplex virus 1 or 2.¹² Zalcitabine has synergy with zidovudine, delavirdine, saquinavir, and interferon-a.¹³^–¹⁵ In contrast, zalcitabine has demonstrated antagonism with ribavirin, perhaps through ribavirin’s inhibition of zalcitabine’s phosphorylation.^16,¹⁷ In vitro cytotoxicity from zalcitabine has usually been demonstrated at concentrations of 10 μM or higher, although Molt-4 cells have demonstrated an increased doubling time, decreased cellular content of mitochondrial DNA, and decreased rate of glycolysis at 0.5 or 0.2 μM.¹⁸

The intracellular metabolism of zalcitabine begins with cellular entry through both nucleoside carrier-mediated and non-carrier-mediated mechanisms.¹⁹^–²¹ Zalcitabine then undergoes triphosphorylation by cellular kinases that are also used by 2′-deoxycytidine.²² The process of triphosphorylation occurs in both HIV-infected and HIV-uninfected cell lines.^19,^23,²⁴ Anywhere from 2% to 40% of zalcitabine is converted to its triphosphate form, 2′,3′-dideoxycytidine 5′-triphosphate (ddCTP), depending on the cell line studied.^19,^25,²⁶ Zalcitabine is most efficiently triphosphorylated in resting peripheral blood mononuclear cells, in contrast to zidovudine, which is most efficiently triphosphorylated in activated cells.^27,²⁸ The ddCTP binds to HIV-1 reverse transcriptase with a ^KI of 0.2–0.9 μM^29,³⁰; it does not bind efficiently to host a DNA polymerase, but it has been speculated that zalcitabine’s neurotoxicity may be related to its inhibition of host β and γ DNA polymerases.¹⁸ The efflux of ddCTP from Molt-4 cells follows a biphasic pattern with an initial retention half-life of 2.6 h.²⁵

PHARMACOKINETICS

Zalcitabine has been administered over the dose range of 0.007–0.50 mg/kg, although a clear dose-response relation with peripheral neuropathy at doses of more than 0.01 mg/kg has limited the use of higher doses.³¹^–³⁴ Zalcitabine has linear pharmacokinetics over the dose range of 0.03–0.5 mg/kg.^32,³³ It is ∼70–90% bioavailable following oral administration of zalcitabine oral solution or tablets.^32,³³ The maximum plasma concentration of zalcitabine after an oral dose of 1.5 mg is 0.12 μM, which occurs 0.8 h after dosing. Administration of zalcitabine with food decreases the maximum plasma concentration by 39%, prolongs the time to achieve maximum concentrations to 1.6 h, and decreases the plasma concentration area under the curve (AUC) by 14%.⁹

Zalcitabine is rapidly eliminated, with a total body clearance of ∼250 mL min⁻¹ m⁻² after single and multiple doses. In patients with normal renal function, the plasma elimination half-life is 1–3 h and no significant drug accumulation was noted after 14 days of intravenous dosing.^32,³³ As a result, zalcitabine is recommended for every-8-hour oral dosing. Two small studies of zalcitabine dosed twice daily have been published and demonstrated promising activity.^34,³⁵ However, their sample sizes were small (total 41 subjects) and there was no comparisons with zalcitabine dosed every 8 h.

Zalcitabine reaches a steady-state volume of distribution of 0.5–0.6 L/kg in adults, and less than 4% is bound to plasma proteins.⁹ Zalcitabine concentrations in cerebrospinal fluid approximate 20% of plasma levels.³¹ Zalcitabine does not undergo hepatic metabolism, and ∼75% and 62% of intravenous and oral doses, respectively, are recovered unchanged in the urine over 24 h.³² In seven patients with creatinine clearances of less than 55 mL/min, the plasma half-life of zalcitabine was prolonged to 8.5 h.⁹ Similar pharmacokinetics have been observed in HIV-infected children, although zalcitabine bioavailability is more variable in children (29–100%) than in adults.³⁶

TOXICITY

The reported toxicities of zalcitabine include peripheral neuropathy, stomatitis, rash, and pancreatitis. The major studies of zalcitabine that describe toxicities are summarized in Table 7-1.

Table 7-1 Toxicities Associated with Zalcitabine

Peripheral Neuropathy

The most common toxicity related to zalcitabine is a peripheral neuropathy.³⁷^–⁴⁰ The frequency of peripheral neuropathy is clearly dose related and was reported in up to 100% of subjects receiving zalcitabine 0.03 mg/kg q4h.³⁷ Moderate peripheral neuropathy has been reported in 3–23% of patients taking zalcitabine, and severe peripheral neuropathy has been reported in 0–15%.⁴⁰^–⁴³ In randomized trials comparing zalcitabine-containing and didanosine-containing regimens, the frequency of zalcitabine-associated severe peripheral neuropathy was higher (5% vs 1%⁴² and 15.0% vs 6.6%,⁴⁴ respectively). Two small studies observed infrequent peripheral neuropathy in subjects receiving zalcitabine 1.125 mg twice daily for up to 48 weeks (1/41 subjects).^34,³⁵ Baseline characteristics associated with a higher frequency of zalcitabine-associated peripheral neuropathy include a lower absolute CD4+ T-lymphocyte number,³⁹ diabetes mellitus,⁴⁵ lower baseline vitamin B¹² levels, heavy alcohol consumption, and a history of symptomatic peripheral neuropathy.⁴⁶ Symptoms typically begin at a mean of 10–18 weeks after initiating zalcitabine⁴⁵^–⁴⁷ and most commonly involve the distal lower extremities.^45,⁴⁶ The symptoms usually begin in a symmetrical stocking distribution, with numbness, aching, and burning dysesthesias. On examination, patients may have diminished sensation in response to light touch, pinprick, temperature, and vibration; and up to 60% may have absent ankle deep tendon reflexes.^45,⁴⁸ Nerve conduction studies reveal a sensory axonal neuropathy with decreased to absent sensory nerve action potentials and normal distal latencies and velocities.⁴⁸ The symptoms of zalcitabine-associated peripheral neuropathy may worsen for up to 5 weeks following its discontinuation^31,⁴⁸ but then slowly improve. More severe neuropathic symptoms may not return to baseline. If symptoms resolve, most patients are able to tolerate the careful reintroduction of half-dose zalcitabine.⁴⁵ Preexisting zalcitabine-associated peripheral neuropathy may predispose to neuropathic exacerbation on didanosine,⁴⁹ so didanosine should be substituted for zalcitabine with caution.

Stomatitis

Stomatitis was reported in eight of 20 patients in the first dose-escalation phase I trial of zalcitabine.³¹ The ulcerations most commonly occur on the buccal mucosa, soft palate, tongue, or pharynx. They are usually self-limited and resolve with continued therapy. In large clinical trials utilizing zalcitabine at doses of 0.75 mg q8h, the reported frequency of moderate to severe oral ulcerations is 2–4%.⁴⁰^–⁴² ⁵⁰ One case of more severe esophageal ulceration that required discontinuation of zalcitabine has also been reported.⁵¹

Rash

Rash was reported in 14 of 20 patients in the first dose-escalation phase I trial of zalcitabine.³¹ The rash is most commonly an erythematous, maculo-papular eruption over the trunk and extremities. It usually begins after 10–14 days of zalcitabine therapy and is self-limited. Larger trials have not reported the frequency of zalcitabine-associated rash, presumably because it is mild and self-limited. Skin biopsies of the rash reveal perivascular lymphocytic infiltrates.⁵²

Pancreatitis

Pancreatitis has been reported infrequently in zalcitabine-treated patients. Large trials suggest a frequency of 0.5–3.0%.^38,^39,^41,⁴² Trials that have randomized subjects to either zalcitabine or didanosine suggest that zalcitabine-associated pancreatitis occurs less commonly (0.5% vs 1%⁴¹ and 0.5% vs 2.2%,⁵³ respectively). One case of fatal zalcitabine-associated pancreatitis has been reported.³⁹

Other Toxicities

Miscellaneous toxicities attributed to zalcitabine include cardiomyopathy,⁹ anaphylactoid reactions,³⁸ fever,³⁸ reversible hearing loss,³⁸ arthralgias,⁵⁰ and myalgias.⁵⁰ Zalcitabine’s potential to cause hepatotoxicity remains unclear; transaminase elevations led to drug discontinuation in one subject,⁴⁰ and a large randomized trial revealed transaminase elevations in 7.1% of subjects receiving zalcitabine/zidovudine, 5% of subjects receiving didanosine/zidovudine, and 5.1% of subjects receiving zidovudine alone.⁴² There are no available data regarding the use of zalcitabine during pregnancy.

EFFICACY

Zalcitabine has been evaluated extensively as monotherapy and two- and three-drug combinations in HIV-infected subjects. The results of major efficacy studies are summarized in Table 7-2.

Table 7-2 Major Activity and Efficacy Trials Evaluating Zalcitabine Monotherapy and Combination Therapy

Zalcitabine Monotherapy

Many early trials evaluated zalcitabine monotherapy in subjects with relatively late-stage HIV infection.^31,³⁷^–⁴⁰ ^,54 The designs of these trials included dose-escalation studies,^31,³⁷ zalcitabine alternating with zidovudine,³⁸ and comparisons of zalcitabine monotherapy with zidovudine,^39,^40,⁵⁵ didanosine,⁵⁶ or saquinavir⁵⁴ monotherapies. Increases in absolute CD4+ T-lymphocyte number of zalcitabine-treated subjects were extremely small,³¹ if they changed at all from baseline.³⁷ In patients with severe acquired immunodeficiency syndrome (AIDS)-related complex (ARC) or AIDS and 48 weeks or less of prior zidovudine, subjects randomized to zalcitabine had less decline in absolute CD4+ T lymphocytes than zidovudine-treated subjects at 28 weeks.³⁹

In contrast to the modest absolute CD4+ T-lymphocyte response in zalcitabine-treated subjects, serum p24 antigen levels responded more favorably.^31,^37,³⁸ In one dose-escalation study, most subjects experienced at least a 50% decline from baseline in serum p24 antigen levels.³⁷ Similar results were seen in subjects receiving alternating zalcitabine and zidovudine compared to those receiving zidovudine alone. Zidovudine-experienced subjects were less likely to have p24 antigen suppression, and in the ACTG 155 study no significant difference was noted between zalcitabine- and zidovudine-treated subjects.⁴⁰

The clinical outcomes reported in zalcitabine-treated subjects are variable, and their inconsistency probably reflects the inadequacy of antiretroviral monotherapy. The ACTG 114 study, performed in subjects with ARC or AIDS and less than 3 months of prior zidovudine, reported more frequent progression to AIDS or death in zalcitabine-treated subjects compared to those receiving zidovudine.⁵² Studies ACTG 119 and 155, both performed in subjects with ARC or AIDS and more zidovudine experience (ACTG 119: =48 weeks; ACTG 155: >6 months), revealed no differences in progression to AIDS or death, or survival, between zalcitabine- and zidovudine-treated subjects.^39,⁴⁰ The CPCRA 002 study was performed in subjects with absolute CD4+ T-lymphocyte counts of less than 300 cells/mm³ and either zidovudine intolerance or more than 6 months of prior zidovudine with disease progression. Subjects were randomized to zalcitabine or didanosine monotherapy, and the results suggested a possible survival advantage for zalcitabine over didanosine, with an adjusted relative risk of 0.65 (P = 0.003).⁵⁶ In the NV 14 256 trial subjects were randomized to receive zalcitabine or saquinavir monotherapy, or the combination.⁵⁴ There were no significant differences in plasma HIV RNA levels, CD4+ T-lymphocyte numbers and AIDS-defining events or deaths between the zalcitabine or saquinavir monotherapy arms.