Stavudine, pharmacokinetics

Children Use of stavudine in pediatric patients is supported by evidence from adequate and well-controlled studies of stavudine in adults with additional pharmacokinetic and safety data in pediatric patients. 

In those who are opioid-dependent, methadone can facilitate adherence to HAART regimens. The pharmacokinetics of the tablet formulations of didanosine and stavudine have been studied in 17 individuals taking stable methadone therapy in comparison with 10 untreated controls (33). Methadone reduced the AUCo 6 by 63% for didanosine and by 25% for stavudine and the C ax by 66% and 44% respectively. These effects appeared to result primarily from reduced systemic availability. Trough concentrations of methadone were comparable to those seen in historical controls, suggesting that the nucleoside analogues did not affect methadone disposition. The authors concluded that larger doses of the tablet formulation (or another type of formulation) may be necessary to provide HAART in subjects taking methadone. 

Pharmacokinetics and clinical uses Stavudine is used in HAART regimens. The drug has good oral bioavailability and penetrates most tissues, including the CNS. Dosage adjustment is needed in renal insufficiency. 

Zidovudine had no effect on methadone levels in one study, but there is one report of a patient requiring a modest increase in methadone dose after starting zidovudine. Similarly case reports describe patients requiring a modest increase in methadone dose after starting abacavir. Methadone can increase zidovudine serum levels, and reduce levels of abacavir, stavudine, and didano-sine from the tablet formulation, but not the enteric-coated capsule preparation. Tenofovir, and a single dose of zidovu-dine/lamivudine had no effect on methadone pharmacokinetics. 

A study in 17 subjects taking methadone found that the AUC and maximum levels of stavudine were 23% and 44% lower, respectively, when compared with 10 control subjects. Trough levels of methadone did not differ from historical controls suggesting that stavudine had no effect on methadone pharmacokinetics. ... 

Delavirdine absorption is reduced by the buffered preparation of didanosine. This interaction would not be expected with the enteric-coated preparation of didanosine. Delavirdine does not affect the pharmacokinetics of zidovudine. There is no pharmacokinetic interaction between efavirenz and zidovudine or lamivudine. There is no ciinicaiiy reievant pharmacokinetic interaction between nevirapine and didanosine, iamivudine, stavudine, zaicit-abine or zidovudine. 

Nevirapine 200 mg once daily for 2 weeks then 200 mg twice daily had no effect on the AUC of stavudine 30 to 40 mg twice daily in a study in 22 patients. " Nevirapine appears to have no effect on lamivudine clearance, based on a population pharmacokinetic study. 

Skowron G, Leoung G, Hall DB, Robinson P, Lewis R, Grosso R, Jacobs M, Kerr B, MacGregor T, Stevens M, Fisher A, Odgen R, Yen Uebeiman B. Pharmacokinetic evaluation and short term activity of stavudine, nevirapine, and nelfinavir therapy in HIV-l-infected adults. J Acquir Immune DeSc Syndr 200i) 35, 351. ... 

A study in 10 HIV-positive subjects found that rifabutin 300 mg daily had no significant effects on the pharmacokinetics of the stavudine 30 or... 

Fluconazole has no significant effect on the pharmacokinetics of didanosine or stavudine, but it may cause an increase in serum zidovudine levels although the clinical importance of this is uncertain. Fluconazole serum levels remain unchanged. 

There is no pharmacokinetic interaction between stavudine and fluconazole. No interaction would be expected with other similar NRTIs such as lamivudine and zalcitabine (see Antivirals , (p.772)). 

In a study of 11 HIV-positive patients, oral ganciclovir 1 g three times daily had no significant effect on the pharmacokinetics of stavudine 40 mg twice daily, nor were the pharmacokinetics of ganciclovir affected by the stavudine. There were no serious or severe adverse events attributed to the combination. 

Ganciclovir does not appear to alter the pharmacokinetics of stavudine or zalcitabine. Zalcitabine increased ganciclovir levels to a minor extent, although this is probably not clinically important. 

Jung D, AbdelHameed MH, Teitelbaum P, Dorr A, Griffy K. The pharmacokinetics and safety profile of oral ganciclovir combined with zalcitabine or stavudine in asymptomatic HIV-and CMV-seropositive patients. J Clin Pharmacol (1999) 39, 505-12. 

A study in 10 HIV-positive subjects found that the addition of clarithromycin 500 mg twice daily to stavudine 30 or 40 mg twice daily had no significant effects on the pharmacokinetics of the stavudine and the incidence of adverse effects did not increase. No special precautions would seem necessary if both drugs are given. 

There was no important pharmacokinetic interaction between single doses of emtricitabine 200 mg and stavudine 40 mg in 6 healthy subjects. UK guidelines say that stavudine is not recommended for use as one of the NRHs for initial therapy of HIV because of its toxicity. ... 

The manufacturer of atazanavir -" notes that there was no pharmacokinetic interaction with stavudine. 

Fletcher CV, Yogev Nachman SA, Wiznia A, Pelton S, McIntosh K, Stanley K. Pharmacokinetic characteristics of ritonavir, zidovudine, lamivudine, and stavudine in children with human immunodeficiency virus infection. Pharmacotherapy (2004) 24,453-9. 

In vitro, ribavirin reduced the intracellular activation and antiretroviral activity of stavudine. However, in a study in 5 HIV-positive patients with hepatitis C, ribavirin 800 mg daily had no statistically significant effect on the pharmacokinetics of stavudine (a 45% increase in AUC), and no effect on intracellular activation of stavudine, when compared with similar patients who received placebo. Similarly, no decrease in antiviral activity of stavudine (as assessed by plasma HIV-RNA levels) has been seen when ribavirin was given with interferon for hepatitis C infection in patients with HIV. " Nevertheless, the UK manufacturers of ribavirin continue to recommend that plasma HIV-RNA levels are closely monitored in patients taking ribavirin with stavudine to ensure continued efficacy. In contrast, based on an analysis of data from the adverse event reporting system of the FDA in the US, (see didanosine above), the UK manufacturers of ribavirin consider that concurrent use of stavudine should be avoided to limit the risk of mitochondrial toxicity. The UK manufacturer of stavudine notes that patients co-infected with hepatitis C and treated with interferon alfa and ribavirin may be at increased risk ofNRTI-associated lactic acidosis. Patients at increased risk should be monitored closely. Similarly, the US manufacturer of stavudine states that patients receiving interferon with or without ribavirin and stavudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. ... 

Tenofovir increases the levels of didanosine an increased risk of pancreatitis and peripheral neuropathy has been reported, and a high level of treatment failure. There is no pharmacokinetic interaction between tenofovir and abacavir, emtricitabine, lamivudine or stavudine. However, the combination of tenofovir, lamivudine and abacavir was unexpectedly associated with a high level of treatment failure. Triple-NRTI regimens invoiving tenofovir are not recommended, with the possibie exception of tenofovir, lamivudine and zidovudine. 

Time course Rifampicin induces CYP3A4 at about 15 days, and interaction studies have generally started treatment with protease inhibitors within 15 days of the start of rifampicin therapy. Furthermore, pharmacological tolerance to effects can occur. The problems of variations in pharmacokinetics with time have been illustrated by a study of the effects of rifampicin on the pharmacokinetics of nevirapine in 16 patients coinfected with HTV-1 and tuberculosis [39"]. They took standard antituberculosis therapy and a fixed-dose combination of stavudine, lamivudine, and nevirapine. The median AUC of nevirapine was reduced by rifampicin by 26% at 4 weeks, but by only 7.5% at 10 weeks. The median Crm was reduced by 20% at 4 weeks and by 7.1% at 10 weeks. The authors concluded that the effect of rifampicin on the pharmacokinetics of nevirapine substantially decreases over time. 

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