Nevirapine Systematic (IUPAC) name 11-cyclopropyl-4-methyl-5,11-dihydro-6H- dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one Clinical data Trade names Viramune AHFS/Drugs.com MedlinePlus Pregnancy cat. B: (USA) Legal status ? Routes Oral Pharmacokinetic data Bioavailability 93% ± 9% Metabolism Hepatic Half-life 45 hours Excretion Renal: <6% (Parent drug)
Biliary <5% (Parent drug)
Identifiers CAS number ATC code J05 PubChem DrugBank ChemSpider UNII KEGG ChEMBL Chemical data Formula C15H14N4O Mol. mass 266.888 g/mol SMILES & (what is this?)
As with other antiretroviral drugs, HIV rapidly develops resistance if nevirapine is used alone, so recommended therapy consists of combinations of three or more antiretrovirals.
Nevirapine was discovered by Hargrave et al. at Boehringer Ingelheim Pharmaceuticals, Inc., one of the Boehringer Ingelheim group of companies. It is covered by U.S. Patent 5,366,972 and corresponding foreign patents. Nevirapine was the first NNRTI approved by the U.S. Food and Drug Administration (FDA). It was approved June 21, 1996 for adults and September 11, 1998 for children. It was also approved in Europe in 1997.
Mode of action
Nevirapine falls in the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of antiretrovirals. Both nucleoside and non-nucleoside RTIs inhibit the same target, the reverse transcriptase enzyme, an essential viral enzyme which transcribes viral RNA into DNA. Unlike nucleoside RTIs, which bind at the enzyme's active site, NNRTIs bind allosterically at a distinct site away from the active site termed the NNRTI pocket.
Nevirapine is not effective against HIV-2, as the pocket of the HIV-2 reverse transcriptase has a different structure, which confers intrinsic resistance to the NNRTI class.
Resistance to nevirapine develops rapidly if viral replication is not completely suppressed. The most common mutations observed after nevirapine treatment are Y181C and K103N, which are also observed with other NNRTIs. As all NNRTIs bind within the same pocket, viral strains which are resistant to nevirapine are usually also resistant to the other NNRTIs, efavirenz and delavirdine.
Nevirapine in triple combination therapy has been shown to suppress viral load effectively when used as initial antiretroviral therapy (i.e., in antiretroviral-naive patients). Some clinical trials have demonstrated comparable HIV suppression with nevirapine-based regimens to that achieved with protease inhibitors (PIs) or efavirenz. Although concerns have been raised about nevirapine-based regimens in those starting therapy with high viral load or low CD4 count, some analyses suggest that nevirapine may be effective in these patients.
Nevirapine may also form a useful component of salvage regimens after virological failure, usually in combination with one or more PIs as well as nRTIs, especially in those who have not previously taken an NNRTI.
The most common adverse effect of nevirapine is the development of mild or moderate rash (13%). Severe or life-threatening skin reactions have been observed in 1.5% of patients, including Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity.
Nevirapine may cause severe or life-threatening liver toxicity, usually emerging in the first six weeks of treatment. In 2000, the U.S. Food and Drug Administration issued a black box label on nevirapine, warning that it could cause severe liver damage, including liver failure. Unacceptably high risk of serious liver symptoms in certain patient groups (women with CD4 count >250 and men >400) has led the U.S. DHSS to recommend the restriction of nevirapine use to those at lower risk, unless the benefit to the patient clearly outweighs the risk; although in the 2NN study which found these CD4 limits, the effect was seen only in patients recruited from Thailand. More recent studies on the use of Nevirapine in people with higher CD4 cell counts have come to the following conclusion: Treatment-experienced patients who start NVP-based combination therapy with low pre–ART and high current CD4 cell counts and an undetectable VL have a similar likelihood for discontinuing NVP therapy because of hypersensitivity reactions (HSRs), compared with treatment-naive patients with low CD4 cell counts. This suggests that NVP-based combination therapy may be safely initiated in such patients. However, in similar patients with a detectable VL, it is prudent to continue to adhere to current CD4 cell count thresholds. The U.S. Public Health Service Task Force advocates caution in the use of nevirapine in pregnancy due to toxicity issues, which may be exacerbated during pregnancy.
Nevirapine is an inducer of cytochrome P450 isoenzymes CYP3A4 and CYP2B6. It reduces the levels of several co-administered drugs including the antiretrovirals efavirenz, indinavir, lopinavir, nelfinavir and saquinavir, as well as clarithromycin, ketoconazole, forms of hormonal contraception, and methadone.
Preventing mother-to-child transmission
A single dose of nevirapine given to both mother and child reduced the rate of HIV transmission by almost 50% compared with a very short course of zidovudine (AZT) prophylaxis, in a clinical trial in Uganda. A subsequent study in Thailand showed that prophylaxis with single-dose nevirapine in addition to zidovudine is more effective than zidovudine alone. These and other trials have led the World Health Organization to endorse the use of single-dose nevirapine prophylaxis in many developing world settings as a cost-effective way of reducing mother-to-child transmission. However, in the United States the Ugandan study was deemed flawed  and as of 2006 the FDA has not approved of such nevirapine prophylaxis. Another clinical trial, Using Nevirapine to Prevent Mother-to-Child HIV Transmission During Breastfeeding is scheduled for completion in March 2011.
A major concern with this approach is that NNRTI resistance mutations are commonly observed in both mothers and infants after single-dose nevirapine, and may compromise the response to future NNRTI-containing regimens. A short course of maternal zidovudine/lamivudine is recommended by the U.S. Public Health Service Task Force to reduce this risk.
Controversy in Africa
U.S. President George W. Bush's $500 million plan to help combat the African AIDS epidemic includes nevirapine, among other medications and programs. Nevirapine has also been tested in trials in Africa, some of which have been highly controversial.
Former President of South Africa Thabo Mbeki accused the United States of using Africans as "guinea pigs". Questions regarding the efficacy of the antiretroviral nevirapine when compared with its side effects were the main stated reason for President Mbeki's concern.
Hargrave, K. D.; Peoudfoot, J. R.; Grozinger, K. G.; Cullen, E.; Kapadia, S. R.; Patel, J. R.; Fuchs, V. U.; Mauldin, S. C.; Vitous, S. J.; Behnke, M. L.; et al.; J. Med. Chem. 1991, 34, 2231.
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Névirapine — Structure chimique de la névirapine Général Nom IUPAC 11 cyclopropyl 5,11 dihydro 4 methyl 6H dipyrido[3,2 b:2 ,3 f][l … Wikipédia en Français
Nevirapine — Névirapine Névirapine Structure chimique de la névirapine Général Nom IUPAC 11 cyclopropyl 5,11 dihydro 4 methyl 6H dip … Wikipédia en Français
nevirapine — nevirapine. См. невирапин. (Источник: «Англо русский толковый словарь генетических терминов». Арефьев В.А., Лисовенко Л.А., Москва: Изд во ВНИРО, 1995 г.) … Молекулярная биология и генетика. Толковый словарь.
nevirapine — noun Etymology: perhaps from ne (by reversal of enzyme) + viral + dipyridodiazepinone, class of drugs to which nevirapine belongs Date: 1991 an antiretroviral drug C15H14N4O that inhibits reverse transcriptase and is administered orally in… … New Collegiate Dictionary
nevirapine — ne·vir·a·pine (nə vîrʹə pēn , pĭn) n. A non nucleoside analogue that is used as an antiviral drug in the treatment of HIV infection. [Probably ne , negative prefix + virus + alteration of (diaz)epine.] * * * … Universalium
nevirapine — noun A non nucleoside reverse transcriptase inhibitor used to treat HIV and AIDS … Wiktionary
nevirapine — ne·vi·ra·pine nə vir ə .pēn, vī rə n an antiretroviral drug C15H14N4O that inhibits reverse transcriptase and is administered orally in combination with at least one other antiretroviral in the treatment of infection by HIV 1 and AIDS * * *… … Medical dictionary
nevirapine — /nəˈvɪərəpin/ (say ne vearruhpeen) noun an antiretroviral drug, used especially by HIV positive mothers breastfeeding their HIV negative babies … Australian English dictionary
névirapine — n.f. Médicament antirétroviral … Le dictionnaire des mots absents des autres dictionnaires
nevirapine — noun a non nucleoside reverse transcriptase inhibitor (trade name Viramune) used to treat AIDS and HIV • Syn: ↑Viramune • Hypernyms: ↑non nucleoside reverse transcriptase inhibitor, ↑NNRTI … Useful english dictionary