Zalcitabine dosing

Fischl MA, Richman DD, Saag M, Meng TC, Squires KE, Holden-Wiltse J, Meehan PM (1997) Safety and antiviral activity of combination therapy with zidovudine, zalcitabine, and two doses of interferon-alpha2a in patients with HIV. J Acquit Immune Deflc Syndr Hum Retrovirol 16 247-253... 

NRTls are structural analogues of the natural nucleotides that form the building blocks of RNA and DNA in human cells. Their use as part of HAART has dramatically modified the natural history of HIV infection. They, however, cause a range of drag- or tissue-specific toxicides zidovudine (AZT) causes myopathy zalcitabine (ddC), didanosine (ddl), and lamivudine (3TC) cause neuropathy stavudine (d4T) causes neuropathy or myopathy and lactic acidosis (Dalakas 2001). During phase 1 and 11 trials, the dose-limiting toxicity of didanosine, zalcitabine, and stavudine was identified as peripheral neuropathy (Dalakas 2001). 

Blum AS, Dal Pan GJ et al (1996) Low-dose zalcitabine-related toxic neuropathy frequency, natural history, and risk factors. Neurology 46(4) 999-1003 Bradley WG, Verma A (1996) Painful vascuhtic neuropathy in HlV-1 infection relief of pain with prednisone therapy. Neurology 47(6) 1446-1451 Breen EC (2002) Pro- and anti-inflammatory cytokines in human immunodeficiency virus infection and acquired immunodeficiency syndrome. Pharmacol Ther 95(3) 295-304 Bremer J (1990) The role of carnitine in intracellular metabolism. J Clin Chem Clin Biochem 28(5) 297-301... 

Zalcitabine (ddC) Hivid (anticipated discontinuation of distribution in 2006) 0.375-, 0.75-mg tab 0.75 mg tid CrCI Dose (mL/minute) 10-40 0.75 mg bid less than 10 0.75 mg qday No data on hemodialysis None Peripheral neuropathy stomatitis, lactic acidosis with hepatic steatosis (rare but potentially life-threatening toxicity with use of NRTIs) pancreatitis Renal excretion... 

Combination therapy with antiretrovirals The recommended regimen is one 0.75 mg tablet of zalcitabine orally every 8 hours (2.25 mg zalcitabine total daily dose) in... 

Combination therapy - For toxicities likely to be associated with zalcitabine (eg, peripheral neuropathy, severe oral ulcers, pancreatitis, elevated liver function tests, especially in patients with chronic hepatitis B see Warnings and Precautions), interrupt or reduce dose. For severe toxicities or those persisting after dose reduction, interrupt zalcitabine therapy. For recipients of combination therapy with zalcitabine and other antiretrovirals, base dose adjustments or interruption for either drug on the known toxicity profile of the individual drugs. 

Peripheral neuropathy - Patients developing moderate discomfort with signs or symptoms of peripheral neuropathy should stop zalcitabine. Zalcitabine-associated peripheral neuropathy may continue to worsen despite interruption of therapy. Reintroduce the drug at 50% dose (0.375 mg every 8 hours) only if all findings related to peripheral neuropathy have improved to mild symptoms. Permanently discontinue the drug when patients experience severe discomfort related to peripheral neuropathy or moderate discomfort progresses. If other moderate to severe clinical adverse reactions or lab abnormalities (eg, increased liver function tests) occur, interrupt zalcitabine (or both zalcitabine and the other potential causative... 

Absorption/Distribution Following oral administration to HIV-infected patients, the mean absolute bioavailability of zalcitabine was greater than 80%. The absorption rate of a 1.5 mg oral dose was reduced when administered with food. This resulted in a 39% decrease in mean maximum plasma concentrations (Cmax) 25.2 to 15.5 ng/mL, and a 2-fold increase in time to achieve Cmaxfro mean of 0.8 hours under fasting conditions to 1.6 hours when the drug was given with food. The extent of absorption was decreased by 14% (from 72 to 62 ng h/mL). 

The steady-state volume of distribution following IV administration of a 1.5 mg dose averaged 0.534 L/kg. Cerebrospinal fluid obtained from 9 patients at 2 to 3.5 hours following 0.06 or 0.09 mg/kg IV infusion showed measurable concentrations of zalcitabine. The CSFiplasma concentration ratio ranged from 9% to 37% (mean, 20%), demonstrating drug penetration through the blood-brain barrier. 

Metabolism/Excretion Zalcitabine is phosphorylated intracellularly to zalcitabine triphosphate, the active substrate for HIV-reverse transcriptase. Concentrations of zalcitabine triphosphate are too low for quantitation. Metabolism has not been fully evaluated. Zalcitabine does not appear to undergo a significant degree of metabolism by the liver. Renal excretion appears to be the primary route of elimination, and accounted for approximately 70% of an orally administered dose within 24 hours after dosing. The mean elimination half-life is 2 hours. Total body clearance following an IV dose averages 285 mL/min. Less than 10% of a dose... 

Children - Limited pharmacokinetic data have been reported for 5 HIV-positive children using doses of 0.03 and 0.04 mg/kg administered orally every 6 hours. The mean bioavailability of zalcitabine in this study was 54% and mean apparent systemic clearance was 150 mL/min/m. ... 

Mutagenesis Human peripheral blood lymphocytes were exposed to zalcitabine, and at 1.5 mcg/mL or more, dose-related increases in chromosomal aberrations were seen. Oral doses of zalcitabine at 2500 and 4500 mg/kg were clastogenic in the mouse micronucleus assay. 

Didanosine (ddl) NRTT1 Tablets, 400 mg daily,3 adjusted for weight. 30 min before or 2 h after meals. Separate dosing from fluoroquinolones and tetracyclines by 2 h Peripheral neuropathy, pancreatitis, diarrhea, nausea, hyperuricemia. Possible increase in myocardial infarction Avoid concurrent neuropathic drugs (eg, stavudine, zalcitabine, isoniazid), ribavirin, and alcohol. Do not administer with tenofovir... 

Zalcitabine (ddC) is a cytosine analog with high oral bioavailability (87%) and a serum half-life of 1-2 hours. Intracellular half-life of 2.6 hours necessitates thrice-daily dosing, which limits its usefulness (Figure 49-2). Plasma levels decrease by 25-39% when the drug is administered with food or antacids. The drug is excreted renally. Cerebrospinal fluid concentrations are approximately 20% of those in the plasma. 

After oral administration, the bioavailability of zalcitabine is more than 80%. Food slightly interferes with its absorption. Sixty to eighty percent of the compound is excreted unchanged in the urine. Its (dideoxycytidine S -triphosphate) peak concentrations are at 2-3 h. The primary metabolite is dideoxyuridine, which is <15% of the administered dose. Zalcitabine is indicated in combination with other antiretroviral agents for the treatment of HIV infection. 

Zalcitabine therapy is associated with a dose-dependent peripheral neuropathy that can be treatment-limiting in 10-20% of patients but appears to be slowly reversible if treatment is stopped promptly. The potential for causing peripheral neuropathy constitutes a relative contraindication to use with other drugs that may cause neuropathy, including stavudine, didanosine, and isoniazid. Decreased renal clearance caused by amphotericin B, foscamet, and aminoglycosides may increase the risk of zalcitabine neuropathy. The other major reported toxicity is oral and esophageal... 

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS GANCICLOVIRAfALGANCIC LOVIR 1. T adverse effects with tenofovir, zidovudine and possibly didanosine, lamivudine and zalcitabine 2. Possibly 1 efficacy of ganciclovir 1. Uncertain possibly additive toxicity. Lamivudine may compete for active tubular secretion in the kidneys 2. Uncertain L bioavailability 1. Avoid if possible otherwise monitor FBC and renal function weekly. It has been suggested that the dose of zidovudine should be halved from 600 mg to 300 mg daily. Monitor for peripheral neuropathy, particularly with zalcitabine 2. Uncertain clinical significance if in doubt, consider alternative cytomegalovirus prophylaxis... 

A 36-year-old HIV-positive man had started to take zidovudine and zalcitabine 9 months earlier together with co-trimoxazole as primary prophylaxis against Pneumocystis jiroveci, but switched to indinavir, stavudine, and lamivudine. Two hours after the first dose of indinavir he developed a high fever, generalized myalgia, and malaise and started to vomit. After the second dose he developed shock and cyanosis. 

Dideoxycytidine (DDC, zalcitabine), a nucleoside analogue that also inhibits reverse transcriptase, is more active than zidovudine in vitro, and (unlike zidovudine) does not suppress erythro-poiesis. DDC is not without toxicity, however, and a severe peripheral neurotoxicity, which is dose-related, has been reported. The chemical structures of DDC and of another analogue with similar properties, 2 3 -dideoxyinosine (DDI, didanosine), are presented in Fig. 10.25 (G, H, respectively). 

Zalcitabine, DDC i Peripheral neuropathy (major and dose-limiting)—GI distress, pancreatitis, neutropenia, rash... 

The oral bioavailability of zalcitabine is greater than 80%, and 60 to 80% of the parent compound is recovered unchanged in the urine. Food has a negligible effect on oral bioavailability. Clearance is greatly diminished in patients with compromised renal function, and daily doses should be reduced in this population. The half-life of intracellular dideoxycytidine 5 -triphosphate is estimated to be 2 to 3 hours. It is therefore recommended that zalcitabine be administered every 8 hours in patients with normal renal function. The CSF-plasma concentration ratio ranges from 0.09 to 0.37, although the clinical significance of CSF penetration is not known. 

Zalcitabine toxicides are similar to those of the other dideoxynucleoside analogs didanosine and stavudine. Severe peripheral neuropathy has been reported in up to 15% of patients. Peripheral neuropathy is dose related and more common with preexisting HIV-associated neuropathy and advanced HIV disease. This is a symmetrical dislal sensory neuropathy that begins in the feet but may progress to a stock-ing/glove distribution. Other specific risk factors for neuropathy include alcohol consumption, diabetes, and low vitamin Bi2 concentrations. If the dmg is stopped as soon as symptoms appear, the neuropathy usually stabilizes and should improve or resolve. Pancreatitis occurs rarely with zalcitabine therapy and appears to be less frequent than with didanosine. 

The drug is well absorbed orally and food does not affect bioavailabihty. The drug is largely excreted unchanged in the urine, and the dose must be reduced in patients with impaired renal function. It is recommended that zalcitabine be administered every 8 hours in patients with normal renal function. 

A study in 12 HIV-positive patients given a single 1.5-mg dose of zalcitabine found that cimetidine 800 mg caused a 24% reduction in the renal clearance of zalcitabine (assumed to be due to a reduction in renal tubular secretion) and a 36% increase in the AUC of zalcitabine. These changes are relatively moderate and of uncertain clinical importance. Monitor concurrent use for possible toxicity. 

In a single-dose study, 12 HIV-positive or AIDS patients were given zalcitabine 1.5 mg alone or with probeneeid 500 mg, given 8 and 2 hours before then 4 hours after. The renal clearance of the zalcitabine was decreased 42% by probenecid, its half-life was increased by 47% and its AUC was increased by 54%. ... 

The concurrent use of zalcitabine and probenecid was well tolerated, and because the zalcitabine half-life is short compared to its dosing schedule significant accumulation would not be expected. 

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