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PubMed1999

Quality of life outcomes of saquinavir, zalcitabine and combination saquinavir plus zalcitabine therapy for adults with advanced HIV infection with CD4 counts between 50 and 300 cells/mm3.

BACKGROUND: Benefits in patient health-related quality of life (HRQL) have not yet been demonstrated for combination antiretroviral therapy with protease inhibitors and nucleoside analogues. This double-blind study evaluated zalcitabine or saquinavir monotherapy and combination saquinavir plus zalcitabine therapy on HROL of human immunodeficiency virus (HIV)-infected adults. METHODS: 940 HIV-infected patients (CD4 counts 50-300 cells/mm3) who had discontinued zidovudine therapy (for intolerance or treatment failure) were randomized to one of three regimens: zalcitabine 0.75 mg every 8 h; saquinavir 600 mg every 8 h; or combination zalcitabine 0.75 mg plus saquinavir 600 mg every 8 hours. HRQL was measured at baseline, 24 and 48 weeks using the Medical Outcome Study HIV Health Survey (MOS-HIV). The primary endpoints were the physical and mental health summary scores (PHS; MHS) of the MOS-HIV as well as a global visual analogue scale (VAS) score. RESULTS: After 24 weeks, the zalcitabine-treated patients demonstrated significantly greater decreases in PHS scores (-4.4 +/- 0.6; saquinavir: -1.3 +/- 0.6; zalcitabine plus saquinavir: -1.7 +/- 0.6; P < 0.0001) and MHS scores (-2.2 +/- 0.5; saquinavir: -1.0 +/- 0.5; zalcitabine plus saquinavir: -0.5 +/- 0.5; P = 0.032) compared to saquinavir and zalcitabine plus saquinavir treated patients. No differences were observed on the VAS (P = 0.172). Nine of 10 MOS-HIV subscales demonstrated results consistent with the primary endpoints. After 48 weeks, a statistically significant difference between the saquinavir-treated groups and the zalcitabine monotherapy group was observed for PHS scores (zalcitabine: -5.8 +/- 0.6; saquinavir: -4.1 +/- 0.6; zalcitabine plus saquinavir: -3.5 +/- 0.6; P = 0.014). CONCLUSIONS: Saquinavir monotherapy and combination saquinavir plus zalcitabine demonstrated a benefit in HRQL relative to zalcitabine monotherapy in patients with prior zidovudine therapy. The HRQL findings are concordant with improved survival and reduced clinical progression of HIV infection found in this study.

Anti-HIV Agents↗
PubMed2000

Zidovudine (AZT) versus AZT plus didanosine (ddI) versus AZT plus zalcitabine (ddC) in HIV infected adults.

BACKGROUND: Zidovudine (AZT) monotherapy was the first antiretroviral drug to be tested widely. The next two drugs to be developed were didanosine (ddI) and zalcitabine (ddC). OBJECTIVES: To assess the effects of zidovudine (AZT), zidovudine plus didanosine (ddI) and zidovudine plus zalcitabine (ddC) on HIV disease progression and survival. SEARCH STRATEGY: Investigators and pharmaceutical companies were contacted, and MEDLINE searches were supplemented by searching conference abstracts. SELECTION CRITERIA: Randomised controlled trials comparing any two of AZT plus ddI, AZT plus ddC or AZT alone in participants with or without AIDS which collected information on deaths and new AIDS events. DATA COLLECTION AND ANALYSIS: Individual patient data with, wherever possible, follow-up obtained beyond that previously published were obtained and checked for internal consistency and consistency with any published reports; any apparent discrepancies were resolved with the trialists. Time to death and to disease progression (defined as a new AIDS-defining event or prior death) were analysed on an intention to treat basis, stratified to avoid direct comparisons between participants in different trials. MAIN RESULTS: Six trials were included in the meta-analysis. During a median follow-up of 29 months, 2904 individuals progressed, of whom 1850 died. The addition of ddI to AZT delayed both progression (RR 0.74; 95% CI 0.67 to 0.82, P<0.0001) and death (RR 0.72; 95% CI 0.64 to 0.82, P<0.0001). Likewise, the addition of ddC to AZT also delayed progression (RR 0. 86; 95% CI 0.78 to 0.94, P=0.001) and death (RR 0.87; 95% CI 0.77 to 0.98, P=0.02). After 3 years the estimated percentages alive and without a new AIDS event were 53% for AZT+ddI, 49% for AZT+ddC and 44% for AZT alone; the percentages alive were 68%, 63% and 59% respectively. Five of the six trials involved randomised comparisons of AZT+ddI versus AZT+ddC: in these, the AZT+ddI regimen had greater effects on disease progression (P=0.004) and death (P=0.009). REVIEWER'S CONCLUSIONS: The use of ddI and, to a lesser extent, ddC delayed both HIV disease progression and death, at least when added to AZT.

Adult↗
PubMed1999

Quality of life outcomes of combination zalcitabine-zidovudine, saquinavir-zidovudine, and saquinavir-zalcitabine-zidovudine therapy for HIV-infected adults with CD4 cell counts between 50 and 350 per cubic millimeter. PISCES (SV14604) Study Group.

BACKGROUND: This double-blind study evaluated treatment with zalcitabine-zidovudine, saquinavir-zidovudine, or saquinavir-zalcitabine-zidovudine on the health-related quality of life of HIV-infected adults with CD4 cell counts between 50 and 350 cells/mm3. METHODS: Nine hundred and ninety-three HIV-infected male or female quality of life substudy patients aged 18 years or older, with CD4 cell counts between 50 and 350 cells/mm3 naïve to antiretroviral therapy or with less than 16 weeks of zidovudine therapy, were randomly assigned to one of three daily regimens: zalcitabine 0.75 mg and zidovudine 200 mg every 8 h (ddC/ZDV); saquinavir 600 mg and zidovudine 200 mg every 8 h (SQV/ZDV); or saquinavir 600 mg, zalcitabine 0.75 mg and zidovudine 200 mg every 8 h (SQV/ddC/ZDV). The health-related quality of life was measured using the Medical Outcome Study HIV (MOS-HIV) Health Survey subscale and physical and mental health summary scores, and a global visual analogue scale (VAS) score. The primary health-related quality of life endpoints were the MOS-HIV physical and mental health summary scores. RESULTS: After 24 weeks of treatment, no statistically significant differences were observed between the three treatment groups on physical health and mental health summary scores (global test P = 0.118). After 48 weeks of treatment, statistically significant differences among the groups were observed for physical health and mental health summary scores (global test P = 0.020); no change in physical health summary scores from the baseline were seen in the triple combination therapy, whereas the ddC/ZDV combination therapy group showed decreases from baseline in physical health summary scores (P = 0.008). Six of the 10 individual MOS-HIV subscale scores and the VAS scores showed results consistent with the physical health summary endpoints after 48 weeks of therapy. No statistically significant differences in baseline to 48 week changes in MOS-HIV subscale or summary scores were seen between the ddC/ZDV and SQV/ZDV groups (P > 0.05). CONCLUSIONS: Patients on triple combination therapy maintained their quality of life over 48 weeks compared with significant decreases in the quality of life for ddC/ZDV combination therapy.

Adult↗
PubMed1996

The effect of probenecid on the pharmacokinetics of zalcitabine in HIV-positive patients.

PURPOSE: The purpose of this study was to determine the potential effect of probenecid on the pharmacokinetics of zalcitabine in HIV-positive patients. METHODS: Twelve patients received single oral 1.5 mg doses of zalcitabine alone and during probenecid treatment (500 mg at 8 and 2 hours before and 4 hours after zalcitabine dosing) in an open-label, randomized two-way crossover study with a one-week washout period between treatments. Serial blood and urine samples were collected over a 24 hour period and assayed for zalcitabine by a modified GC/MS method. RESULTS: Coadministration of probenecid with zalcitabine resulted in a decrease in mean (%CV) renal clearance of zalcitabine from 310 (28%) ml/min when zalcitabine was given alone to 180 (22%) ml/min with probenecid and a prolonged half-life from 1.7 hours to 2.5 hours. Mean AUCs increased from 59 ng.h/ml when zalcitabine was given alone to 91 ng.h/ml when given with probenecid. Considering the short half-life of zalcitabine (1-3 hours) relative to its dosing schedule, the pharmacokinetic changes observed in this study are not expected to result in significant accumulation during chronic dosing. CONCLUSIONS: The results of this study show that co-administration of probenecid with zalcitabine results in a moderate decrease in renal clearance of zalcitabine due to inhibition of renal tubular secretion and a 50% increase in drug exposure. Although well tolerated in this single-dose study, patients taking this combination should be monitored closely for signs of toxicity and dosage reduction should be considered if warranted.

Administration, Oral↗
PubMed2006

Altered pharmacokinetics of zalcitabine by concurrent use of NSAIDs in rats.

AIM: To investigate the pharmacokinetic interactions between zalcitabine and nonsteroidal anti-inflammatory drugs (NSAIDs) in rats. METHODS: Zalcitabine was administered to rats via an iv injection (20 mg/kg) in the presence or absence of ketoprofen or naproxen (20 mg/kg), and the pharmacokinetic parameters were determined by using non-compartmental analysis. RESULTS: Compared with the control (zalcitabine alone), pretreatment with ketoprofen or naproxen 30 min prior to intravenous administration of zalcitabine significantly altered the pharmacokinetic profiles of zalcitabine in rats. Renal clearance of zalcitabine was reduced by approximately 3-4-fold in the presence of ketoprofen or naproxen. Consequently, systemic exposure (AUC) to zalcitabine in the rats pretreated with ketoprofen or naproxen was significantly greater than that for the control group given zalcitabine alone. The terminal plasma half-life of zalcitabine was also prolonged by 4-5-fold in the presence of ketoprofen or naproxen. CONCLUSION: The NSAIDs ketoprofen and naproxen effectively altered the pharmacokinetics of zalcitabine. Therefore, concomitant use of ketoprofen or naproxen in patients being treated with zalcitabine may necessitate close monitoring for potential drug interactions.

Animals↗
PubMed1997

Zalcitabine. An update of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in the management of HIV infection.

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 enzyme 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 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.

Adult↗
PubMed2007

Uridine supplementation antagonizes zalcitabine-induced microvesicular steatohepatitis in mice.

UNLABELLED: Zalcitabine is an antiretroviral nucleoside analogue that exhibits long-term toxicity to hepatocytes by interfering with the replication of mitochondrial DNA (mtDNA). Uridine antagonizes this effect in vitro. In the present study we investigate the mechanisms of zalcitabine-induced hepatotoxicity in mice and explore therapeutic outcomes with oral uridine supplementation. BalbC mice (7 weeks of age, 9 mice in each group) were fed 0.36 mg/kg/d of zalcitabine (corresponding to human dosing adapted for body surface), or 13 mg/kg/d of zalcitabine. Both zalcitabine groups were treated with or without Mitocnol (0.34 g/kg/d), a dietary supplement with high bioavailability of uridine. Liver histology and mitochondrial functions were assessed after 15 weeks. One mouse exposed to high dose zalcitabine died at 19 weeks of age. Zalcitabine induced a dose dependent microvesicular steatohepatitis with abundant mitochondria. The organelles were enlarged and contained disrupted cristae. Terminal transferase dUTP nick end labeling (TUNEL) assays showed frequent hepatocyte apoptosis. mtDNA was depleted in liver tissue, cytochrome c-oxidase but not succinate dehydrogenase activities were decreased, superoxide and malondialdehyde were elevated. The expression of COX I, an mtDNA-encoded respiratory chain subunit was reduced, whereas COX IV, a nucleus-encoded subunit was preserved. Uridine supplementation normalized or attenuated all toxic abnormalities in both zalcitabine groups, but had no effects when given without zalcitabine. Uridine supplementation was without apparent side effects. CONCLUSION: Zalcitabine induces mtDNA-depletion in murine liver with consequent respiratory chain dysfunction, up-regulated synthesis of reactive oxygen species and microvesicular steatohepatitis. Uridine supplementation attenuates this mitochondrial hepatotoxicity without apparent intrinsic effects.

Animals↗
PubMed1996

Mechanism and rate of placental transfer of zalcitabine (2',3'-dideoxycytidine) in Macaca nemestrina.

OBJECTIVE: Our purpose was to determine whether the ant-human immunodeficiency virus drug zalcitabine (2',3'-dideoxycytidine) is actively transferred across the placenta in the near-term Macaca nemestrina. STUDY DESIGN: Constant rate infusions of zalcitabine (1.31 microg/min/kg) and antipyrine (66.7 microg/min/kg) were administered to the dam through the femoral vein (n = 4) or to the fetus through the carotid artery (n = 3) in a randomized cross-over design. Zalcitabine was also administred at a 10-fold higher infusion rate to the dam (n = 3). The effect of zidovudine on the transplacental transfer of zalcitabine was studied by coinfusing the two drugs to the dam (n = 2). Samples from maternal plasma, fetal plasma, and amniotic fluid were collected at regular intervals during the 30-hour infusions. RESULTS: The maternal-fetal transfer clearance of zalcitabine (0.41 +/- 0.16 ml/min/kg) was not significantly different from the fetal-maternal transfer clearance of the drug (0.66 +/ 0.30 ml/min/kg). Moreover, the steady-state fetal-maternal plasma concentration ratios of zalcitabine after the low 0.58 +/- 0.06) and high (0.66 +/- 0.10) infusion rates to the dam were similar. This ratio was not substantially changed (0.69) when zalcitabine was coadministered with zidovudine. The placental transfer rate of zalcitabine was 11% (+/-4%) that of antipyrine. CONCLUSION: The placental transfer of zalcitabine is passive and unaffected by simultaneous administration of zidovudine. In Macaca nemestrina the average fetal exposure to zalcitabine is approximately 60% of the maternal exposure.

Amniotic Fluid↗
PubMed1997

Effect of pregnancy, mode of administration and neonatal age on the pharmacokinetics of zalcitabine (2', 3'-dideoxycytidine) in the pigtailed macaque (Macaca nemestrina).

Our objective was to determine the effect of pregnancy, mode of administration and neonatal age on the pharmacokinetics of the anti-HIV drug zalcitabine (2',3'-dideoxycytidine; ddC) in the pigtailed macaque (Macaca nemestrina). Zalcitabine was administered as an i.v. bolus dose to pregnant dams (n = 3) at term and at 6 weeks post-partum. No significant differences were found between the pre- and post-partum systemic plasma clearance, steady-state volume of distribution or terminal plasma half-life of zalcitabine, indicating that pregnancy does not affect the pharmacokinetics of the drug in the macaque. The observed maternal plasma, fetal plasma and amniotic fluid concentration-time profiles were compared with profiles that were simulated using pharmacokinetic parameter estimates obtained in an earlier constant i.v. infusion study in pregnant macaques. The fetal:maternal ratio of the area under the simulated zalcitabine plasma concentration-time profile after an i.v. bolus dose (0.58) was close to the earlier observed fetal:maternal steady-state plasma concentration ratio after i.v. infusion of the drug (0.58 +/- 0.05). The excellent agreement between observed and simulated fetal:maternal ratio of zalcitabine demonstrates that the steady-state infusion experimental design can be used to estimate the drug exposure to the fetus after a single dose. To determine the influence of age on the pharmacokinetics of zalcitabine, the drug was administered as a single i.v. bolus dose to four infant macaques serially at the ages of 1-2 weeks, 1 month and 4 months. The systemic plasma clearance of zalcitabine was significantly smaller and the terminal plasma half-life significantly longer at age 1-2 weeks than at 1 and 4 months of age. If replicated in humans, these substantial age-dependent changes in the pharmacokinetics of zalcitabine would warrant smaller and less frequent dosing with zalcitabine in HIV-infected neonates than in older children and adults.

Aging↗
PubMed1993

Zalcitabine compared with zidovudine in patients with advanced HIV-1 infection who received previous zidovudine therapy.

OBJECTIVE: To evaluate the safety and efficacy of zalcitabine (also known as dideoxycytidine [ddC]) in patients with advanced human immunodeficiency virus (HIV) infection. DESIGN: Open-label, randomized study. SETTING: AIDS Clinical Trials Units, university-affiliated medical centers, and private practice groups. PATIENTS: Patients with the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex who had tolerated zidovudine for 48 weeks or more. INTERVENTION: Fifty-nine patients received zidovudine (500 to 1200 mg/d) and 52 patients received zalcitabine (2.25 mg/d). MEASUREMENTS: The primary end points were survival and time to an AIDS-defining event or death. RESULTS: Because significantly more patients withdrew from zidovudine therapy, the median duration of treatment was greater in the zalcitabine group than in the zidovudine group (279.0 days compared with 174.5 days; P = 0.001). The estimated 12-month, event-free probabilities were 53% for the zalcitabine group and 57% for the zidovudine group (relative risk, 1.02; 95% CI, 0.5 to 2.2). The estimated 12-month survival rates were 81% for the zalcitabine group and 75% for the zidovudine group (relative risk, 1.39; CI, 0.5 to 3.8). The rate of decline in CD4 lymphocyte counts was significantly slower in the zalcitabine group than in the zidovudine group (-0.08 cells/day compared with -0.17 cells/day). Patients in the zalcitabine group had gained an average of 0.5 kg at week 20 and 0.4 kg at week 24, whereas patients in the zidovudine group had lost an average of 1.8 kg at week 20 and 2.4 kg at week 24 (P = 0.04 and P = 0.05, respectively). Moderate to severe peripheral neuropathy and ulcerative stomatitis occurred in 10 and 9 patients, respectively, in the zalcitabine group. CONCLUSIONS: The sample size for this study was smaller than planned, and no differences in survival and clinical end points were found. Slower rates of decline in CD4 lymphocyte counts and weight, however, were noted for the zalcitabine group.

Adult↗
PubMedDate not supplied

Is there a pharmacokinetic interaction between foscarnet and zalcitabine during concomitant administration?

Foscarnet, an antiviral agent used in the treatment of cytomegalovirus infection, and zalcitabine, an antiretroviral nucleoside analogue used in the treatment of human immunodeficiency virus infection, are commonly used concomitantly. Foscarnet and zalcitabine may interact pharmacokinetically, as both compounds are partially eliminated by renal tubular secretion. Owing to dose-related toxicities associated with these two drugs, it is essential that we have data regarding their pharmacokinetic disposition during concomitant therapy. Twelve patients randomly received either foscarnet (four doses) or zalcitabine (five doses) (Phase 1), followed by concomitant foscarnet (four doses) and zalcitabine (six doses) (Phase 2), followed by dosing with the drug not received in Phase 1 (Phase 3). Following the last dose in each phase of the study, serial plasma samples were collected over 8 hours for zalcitabine and over 12 hours for foscarnet to determine the pharmacokinetics of each drug using noncompartmental analysis. Foscarnet plasma and urine levels were determined using high-performance liquid chromatography, and zalcitabine levels were determined using radioimmunoassay. No clinically significant alterations in the pharmacokinetics of foscarnet or zalcitabine occurred in this study. Thus despite the potential for foscarnet and zalcitabine to compete for renal tubular secretion, no apparent pharmacokinetic interaction exists between these two drugs at the clinically relevant doses studied.

Administration, Oral↗
PubMed1994

A comparative trial of didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection. The Terry Beirn Community Programs for Clinical Research on AIDS.

BACKGROUND: Both didanosine and zalcitabine are commonly used to treat patients with human immunodeficiency virus (HIV) infection who cannot tolerate zidovudine treatment or who have had disease progression despite it. The relative efficacy and safety of these second-line therapies are not well defined. METHODS: In this multicenter, open-label trial we randomly assigned 467 patients who previously received zidovudine and had 300 or fewer CD4 cells per cubic millimeter or a diagnosis of the acquired immunodeficiency syndrome (AIDS) to treatment with either didanosine (500 mg per day) or zalcitabine (2.25 mg per day). RESULTS: After a median follow-up of 16 months, disease progression or death occurred in 157 of 230 patients assigned to didanosine and 152 of 237 patients assigned to zalcitabine, for a relative risk of 0.93 for the zalcitabine group as compared with the didanosine group (P = 0.56), which decreased to 0.84 (P = 0.15) after adjustment for the CD4 count, Karnofsky score, and presence of AIDS at base line. There were 100 deaths in the didanosine group and 88 in the zalcitabine group, for a relative risk of 0.78 (P = 0.09) and an adjusted relative risk of 0.63 (P = 0.003). A majority of patients in each group (66 percent) had at least one adverse event during treatment (153 patients taking didanosine and 157 taking zalcitabine). Peripheral neuropathy and stomatitis occurred more often with zalcitabine and diarrhea and abdominal pain more frequently with didanosine. CONCLUSIONS: For patients with HIV infection who have not responded to treatment with zidovudine, zalcitabine is at least as efficacious as didanosine in delaying disease progression and death.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Pharmacokinetics and distribution over the blood-brain barrier of zalcitabine (2',3'-dideoxycytidine) and BEA005 (2', 3'-dideoxy-3'-hydroxymethylcytidine) in rats, studied by microdialysis.

Microdialysis was applied to sample the unbound drug concentration in the extracellular fluid in brain and muscle of rats given zalcitabine (2',3'-dideoxycytidine; n = 4) or BEA005 (2', 3'-dideoxy-3'-hydroxymethylcytidine; n = 4) (50 mg/kg of body weight given subcutaneously). Zalcitabine and BEA005 were analyzed by high-pressure liquid chromatography with UV detection. The maximum concentration of zalcitabine in the dialysate (Cmax) was 31.4 +/- 5. 1 microM (mean +/- standard error of the mean) for the brain and 238. 3 +/- 48.1 microM for muscle. The time to Cmax was found to be from 30 to 45 min for the brain and from 15 to 30 min for muscle. Zalcitabine was eliminated from the brain and muscle with half-lives 1.28 +/- 0.64 and 0.85 +/- 0.13 h, respectively. The ratio of the area under the concentration-time curve (AUC) (from 0 to 180 min) for the brain and the AUC for muscle (AUC ratio) was 0.191 +/- 0.037. The concentrations of BEA005 attained in the brain and muscle were lower than those of zalcitabine, with Cmaxs of 5.7 +/- 1.4 microM in the brain and 61.3 +/- 12.0 microM in the muscle. The peak concentration in the brain was attained 50 to 70 min after injection, and that in muscle was achieved 30 to 50 min after injection. The half-lives of BEA005 in the brain and muscle were 5.51 +/- 1.45 and 0.64 +/- 0.06 h, respectively. The AUC ratio (from 0 to 180 min) between brain and muscle was 0.162 +/- 0.026. The log octanol/water partition coefficients were found to be -1.19 +/- 0.04 and -1.47 +/- 0.01 for zalcitabine and BEA005, respectively. The degrees of plasma protein binding of zalcitabine (11% +/- 4%) and BEA005 (18% +/- 2%) were measured by microdialysis in vitro. The differences between zalcitabine and BEA005 with respect to the AUC ratio (P = 0.481), half-life in muscle (P = 0.279), and level of protein binding (P = 0.174) were not statistically significant. The differences were statistically significant in the case of the half-life in the brain (P = 0.032), clearance (P = 0.046), volume of distribution (P = 0.027) in muscle, and octanol/water partition coefficient (P = 0.019).

Animals↗
PubMed1995

Health status and function with zidovudine or zalcitabine as initial therapy for AIDS. A randomized controlled trial. Roche 3300/ACTG 114 Study Group.

OBJECTIVE: To evaluate the functional and health status implications of prescribing zalcitabine or zidovudine for initial therapy of acquired immunodeficiency syndrome (AIDS). DESIGN: A substudy of a randomized controlled trial. SETTING: Private and public clinics and referral centers. PATIENTS: Had human immunodeficiency virus (HIV) infection, less than 0.20 x 10(9)/L (200 microliters) CD4+ cells, and either a history of Pneumocystis carinii pneumonia or symptoms of HIV infection. Fifty-eight percent (338/668) of main study enrollees representing 90% of enrollees at participating sites were included in this substudy. INTERVENTIONS: Either zalcitabine at 0.75 mg every 8 hours plus inactive capsules identical in appearance to zidovudine or zidovudine at 200 mg (later 100 mg) every 4 hours plus inactive tablets identical in appearance to zalcitabine. MAIN OUTCOME MEASURES: Results of a periodically completed self-report survey instrument containing specific questions about symptom impact, disability, work, functioning, and utilization as well as nine health and functioning scales adapted from the Medical Outcomes Study (MOS). RESULTS: Zalcitabine recipients were twice as likely to undergo an invasive procedure (P = .004) or be admitted to hospital (P = .01). Zalcitabine recipients reported greater than 40% more symptoms that interfered with activity (P = .001) and greater than 50% more disability days (P < .01). They also had a 7% lower employment rate and a 35% lower monthly income. Average observed health status scores were lower in zalcitabine recipients overall, but especially in the early portion of the study. New methods for combining survival and health status data showed that, over 76 weeks of study, a typical zidovudine recipient spent about 4 (10%) more weeks with at least the typical health state than did a typical zalcitabine recipient. CONCLUSIONS: Zidovudine has substantial advantages over zalcitabine in initial monotherapy of AIDS in terms of functional outcomes such as symptoms impact, disability, work, utilization, and health status. In this case, the differences in functional outcomes presaged differences in physiological and clinical measures. The inclusion of functional outcomes can greatly improve the information available from a clinical trial.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Zalcitabine population pharmacokinetics: application of radioimmunoassay.

Zalcitabine population pharmacokinetics were evaluated in 44 human immunodeficiency virus-infected patients (39 males and 5 females) in our immunodeficiency clinic. Eighty-one blood samples were collected during routine clinic visits for the measurement of plasma zalcitabine concentrations by radioimmunoassay (1.84+/-1.24 samples/patient; range, 1 to 6 samples/patient). These data, along with dosing information, age (38.6+/-7.13 years), sex, weight (79.1+/-15.0 kg), and estimated creatinine clearance (89.1+/-21.5 ml/min), were entered into NONMEM to obtain population estimates for zalcitabine pharmacokinetic parameters. The standard curve of the radioimmunoassay ranged from 0.5 to 50.0 ng/ml. The observed concentrations of zalcitabine in plasma ranged from 2.01 to 8.57 ng/ml following the administration of doses of either 0.375 or 0.75 mg. A one-compartment model best fit the data. The addition of patient covariates did not improve the basic fit of the model to the data. Oral clearance was determined to be 14.8 liters/h (0.19 liter/h/kg; coefficient of variation [CV] = 23.8%), while the volume of distribution was estimated to be 87.6 liters (1.18 liters/kg; CV = 54.0%). We were also able to obtain individual estimates of oral clearance (range, 8.05 to 19.8 liters/h; 0.11 to 0.30 liter/h/kg) and volume of distribution (range, 49.2 to 161 liters; 0.43 to 1.92 liters/kg) of zalcitabine in these patients with the POSTHOC option in NONMEM. Our value for oral clearance agrees well with other estimates of oral clearance from traditional pharmacokinetic studies of zalcitabine and suggests that population methods may be a reasonable alternative to these traditional approaches for obtaining information on the disposition of zalcitabine.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Zalcitabine. Clinical pharmacokinetics and efficacy.

Zalcitabine (ddC) was the first drug to be approved under the US Food and Drug Administration's (FDA's) accelerated drug approval process. Zalcitabine is a potent nucleoside analogue inhibitor of reverse transcriptase used in the treatment of HIV infection. It is approximately 10-fold more potent than zidovudine (AZT) on a molar basis in vitro. Zalcitabine is well absorbed orally and reaches maximal plasma concentrations within 1 to 2 hours. In humans it is mainly eliminated by renal excretion of unchanged drug, and patients with renal failure may exhibit a prolonged half-life. A variety of clinical trials have evaluated the efficacy of zalcitabine based on improved survival and decreased frequency of opportunistic infections and on a surrogate marker of HIV disease, the CD4 count, or the concentration of an antigen associated with HIV, p24. Alternating zalcitabine therapy with zidovudine therapy was associated with increased CD4+ lymphocyte counts and reduced plasma p24 antigen levels. Zalcitabine can cause peripheral neuropathy (in 17 to 31% of patients), which is dose-related and is completely reversible when the drug is discontinued. Zalcitabine will continue to play a role in chemotherapeutic approaches to HIV.

Animals↗
PubMed1995

Combination and monotherapy with zidovudine and zalcitabine in patients with advanced HIV disease. The NIAID AIDS Clinical Trials Group.

OBJECTIVE: To compare the safety and efficacy of continuing zidovudine therapy with that of zalcitabine alone or zalcitabine and zidovudine used together. DESIGN: A randomized, double-blind, controlled trial. SETTING: AIDS Clinical Trials units and National Hemophilia Foundation sites. PATIENTS: 1001 patients with symptomatic human immunodeficiency (HIV) disease and 300 or fewer CD4 cells/mm3 or asymptomatic HIV disease and 200 or fewer CD4 cells/mm3 who had tolerated zidovudine therapy for 6 months or more. INTERVENTION: Patients were randomly assigned to receive zidovudine, 600 mg/d; zalcitabine, 2.25 mg/d; or zidovudine, 600 mg/d, and zalcitabine, 2.25 mg/d. MEASUREMENTS: The primary end point was time to disease progression or death. RESULTS: The median follow-up time was 17.7 months. The estimated 12-month event-free rates were 70%, 67%, and 73%, respectively, for the zidovudine, zalcitabine, and combination groups (P = 0.26). A trend analysis showed significantly lower progression rates for combination therapy compared with zidovudine therapy as the pretreatment CD4 cell count increased (P = 0.027). For patients with 150 or more CD4 cells/mm3, those receiving combination therapy were less likely to have disease progression or to die than were those receiving zidovudine (relative risk, 0.51; 95% CI, 0.28 to 0.93; P = 0.029). We observed no difference between the zalcitabine and zidovudine groups (relative risk, 0.74; CI, 0.40 to 1.36; P = 0.33). For patients with 50 to 150 CD4 cells/mm3 or fewer than 50 CD4 cells/mm3, we found no differences among the treatment groups (P = 0.69 and P = 0.57, respectively). Severe toxic effects occurred less frequently among patients with 150 or more CD4 cells/mm3. CONCLUSIONS: We found no overall benefits of zalcitabine used alone or with zidovudine. However, a trend analysis suggested a better outcome for combination therapy compared with zidovudine as the pretreatment CD4 cell count increased.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Lamivudine plus zidovudine compared with zalcitabine plus zidovudine in patients with HIV infection. A randomized, double-blind, placebo-controlled trial. North American HIV Working Party.

OBJECTIVE: To compare the safety and activity of lamivudine plus zidovudine with the safety and activity of zalcitabine plus zidovudine in patients with moderately advanced human immunodeficiency virus (HIV) infection who had received zidovudine. DESIGN: A multicenter, randomized, double-blind, three-arm, 24-week study with a blinded extension through at least 52 weeks. SETTING: 21 sites in the United States, Canada, and Puerto Rico. PATIENTS: 254 patients who had received zidovudine (median duration of previous therapy, 20 months) and had absolute CD4+ cell counts of 100 to 300 cells/mm3. INTERVENTIONS: Patients were randomly assigned to receive one of three regimens: 150 mg of lamivudine twice daily plus 200 mg of zidovudine three times daily (low-dose lamivudine group); 300 mg of lamivudine twice daily plus 200 mg of zidovudine three times daily (high-dose lamivudine group); or 0.75 mg of zalcitabine plus 200 mg of zidovudine three times daily (zalcitabine group). MEASUREMENTS: Immunologic activity was assessed primarily by changes in absolute CD4+ cell counts; virologic activity was assessed by changes in plasma HIV RNA levels as measured by reverse transcriptase polymerase chain reaction. Safety of the treatment regimens was assessed through the reporting of adverse events. RESULTS: 78% of patients completed 24 weeks of study treatment, and 63% of patients completed 52 weeks of study treatment. Changes in absolute CD4+ cell counts were significantly better for the low-dose and the high-dose lamivudine groups than for the zalcitabine group (median changes at 52 weeks were +42.5 cells/mm3 in the low-dose lamivudine group, +23.33 cells/mm3 in the high-dose lamivudine group, and -29.58 cells/mm3 in the zalcitabine group). Suppression of plasma HIV RNA levels was similar for all groups (median changes at 52 weeks were -0.48 log10 copies/mL in the low-dose lamivudine group, -0.51 log10 copies/mL in the high-dose lamivudine group, and -0.39 log10 copies/mL in the zalcitabine group). No significant differences in safety were seen among the three regimens, although the low-dose lamivudine regimen appeared to be better tolerated than the others. CONCLUSIONS: In patients with HIV infection who had previously received zidovudine, 150 mg of lamivudine plus zidovudine resulted in greater immunologic evidence of benefit than did 0.75 mg of zalcitabine plus zidovudine and was better tolerated than 300 mg of lamivudine plus zidovudine.

Adult↗