Stavudine dosing

There are currently six major antiretroviral drug families (Table 5). Nucleoside reverse transcriptase inhibitors (NRTI) are nucleoside analogs (discussed in more detail in chapter by De Clercq and Neyts, this volume) and were the first approved antiretroviral agents. They include drugs such as AZT, didanosine (ddl), stavudine (d4T), abacavir (ABC), and lamivudine (3TC), the latest used at doses of 300 mg daily as anti-HIV agent (lOOmg/day is the dosing approved for treatment of HBV... 

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). 

Stavudine (d4T) 15-, 20-, 30-, Greater than 60 kg CrCI Dose None Peripheral neuropathy Renal excretion... 

Because urinary excretion is a major route of elimination of stavudine in pediatric patients, the clearance also may be altered in children with renal impairment. Although there are insufficient data to recommend a specific dose adjustment in this patient population, consider a reduction in the dose or an increase in the interval between doses. 

Absorption/Distribution - Following oral administration, stavudine is rapidly absorbed with peak plasma concentrations occurring within 1 hour after dosing. The systemic exposure to stavudine is the same following administration as capsules or solution. Binding to serum proteins was negligible. Oral bioavailability in adults is approximately 86%. The apparent oral volume of distribution is about 66 L. 

Neurologic symptoms Motor weakness has been reported rarely. Most of these cases occurred in the setting of lactic acidosis. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barre syndrome (including respiratory failure). Symptoms may continue or worsen following discontinuation of therapy. Stavudine therapy has been associated with peripheral neuropathy, which can be severe and is dose-related. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, a history of neuropathy, or concurrent neurotoxic drug therapy, including didanosine (see Adverse Reactions). 

Stavudine is an other thymidine analogue with a similar mechanism of action and activity as zidovudine. It can be used in AIDS patients who responded insufficiently to zidovudine or who cannot tolerate zidovudine. Its most prominent dose dependent toxicity is d4T induced neuropathy. 

The adverse effects with which stavudine is most frequently associated are headache, diarrhea, skin rash, nausea, vomiting, insomnia, anorexia, myalgia, and weakness. Peripheral neuropathy consisting of numbness, tingling, or pain in the hands or feet is also common with higher doses of the drug. Significant elevation of hepatic enzymes may be seen in approximately 10 to 15% of patients. Lactic acidosis occurs more frequently with stavudine than with other NRTIs. Viral resistance to stavudine may develop, and cross-resistance to zidovudine and didanosine may occur. 

It is rapidly absorbed after oral administration. Approximately 40 percent of stavudine appears unchanged in the urine through tubular secretion and glomerular filtration. Nonrenal clearance mechanisms account for about 50 percent of elimination of a dose. 

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... 

In combination with other antiretroviral agents, stavudine has caused fatal lactic acidosis in some patients. It is also associated with motor weakness in which case it should be discontinued. Peripheral neuropathy is the most common toxicity associated with stavudine, which is more prevalent at high doses (4mg/kg per day). Neuropathy in these patients generally is associated with numbness, tingling or pain in feet or hands. Patients treated with the combination of stavudine and didanosine may also exhibit liver function abnormalities (hepatic steatosis) and pancreatitis. It may also be associated with the etiology of HIV lipodystrophy syndrome. 

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... 

Use of trimethoprim in high doses should be avoided when coadministering lamivudine. Coadministration of stavudine with drugs causing peripheral... 

ISONIAZID ANTIVIRALS-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS t adverse effects with didanosine and possibly stavudine Additive side-effects Monitor closely for the development of peripheral neuropathy, but no dose adjustment is required... 

Stavudine (t) 1 h). Hepatic toxicity and pancreatitis have been reported, and a dose-related peripheral neuropathy may occur. 

Preferred Pl-based regimens are lopinavir/ritonavir plus lamivudine or emtricitabine plus another NRTI, usually zidovudine, stavudine or abacavir. Alternative combinations include other Pis with or without ritonavir, and two NRTIs. The combination of a protease inhibitor with ritonavir provides inhibition of cytochrome p450 enzymes and permits less frequent dosing of amprenavir, indinavir, lopinavir and saquinavir. Use of ritonavir in this setting is also known as boosting. ... 

A 35-year old Caucasian man with AIDS and multiple opportunistic infections, including Mycobacterium kansasii and Mycobacterium avium complex (MAC) disease developed moderate to severe primary sensorineural hearing loss after 4—5 months of therapy with oral azithromycin 500 mg/day. Other medications included ethambutol, isoniazid, rifabutin, ciprofloxacin, co-trimoxazole, fluconazole, zidovudine (later switched to stavudine), lamivudine, indinavir, methadone, mod-ified-release oral morphine, pseudoephedrine, diphenhydramine, megestrol acetate, trazodone, sorbitol, salbutamol by metered-dose inhaler and nebulizer, ipratropium, and oral morphine solution as needed. Significant improvement of the hearing impairment was documented 3 weeks after drug withdrawal. 

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. 

A 36-year-old woman, who had taken levothyroxine for several years, took stavudine, lamivudine, and indinavir for I month and developed nervousness, palpitation, restlessness, weakness, and weight loss. She had an undetectable serum TSH concentration and raised unbound serum T4 and T3. The dose of levothyroxine was reduced to one-third and then to one-sixth of the previous dose, and the thyroid function tests returned to normal. 

A 46-year-old man with prosthetic cardiac valves took acenocoumarol and later started to take stavudine, lamivudine, and ritonavir 600 mg bd. His INR fell markedly. Although the dose of acenocoumarol was progressively increased to three times the original dose, it was impossible to achieve the previous INR, and ritonavir was withdrawn. 

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