Невирапин

Описание

Nevirapine and its analogues exhibit antiretroviral effect against azothymidine-resistant HIV strains. Nevirapine in combination with ZDV and ddI produced approximately 18% higher CD4 cell counts and a decrease in viral load compared with patients who took ZDV and ddI. Nevirapine is recommended with nucleosides for patients infected with HIV-1 who have experienced clinical or immunologic deterioration. The significant side effects of nevirapine are liver dysfunction and skin rashes.

Химические свойства

Crystalline Solid

Использование

Labelled Nevirapine , a potent (IC50=84nM) and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase. Antiviral.;Labeled Nevirapine, intended for use as an internal standard for the quantification of Nevirapine by GC- or LC-mass spectrometry.

Определение

ChEBI: A dipyridodiazepine that is 5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepine which is substituted by methyl, oxo, and cyclopropyl groups at positions 4, 6, and 11, respectively. A non-nucleoside reverse tr nscriptase inhibitor with activity against HIV-1, it is used in combination with other antiretrovirals for the treatment of HIV infection.

Показания

Nevirapine (Viramune) is approved for the treatment of HIV infection in adults and children as part of a combination therapy. During the first 12 weeks of treatment, patients must be closely monitored for the development of potentially fatal hepatic toxicity (i.e., hepatitis, hepatic necrosis, and hepatic failure) and skin reactions (i.e., Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions). Although these toxicities are rare, common side effects include mild to moderate rash, fever, nausea, fatigue, headache, and elevated liver enzymes.

Приобретенная устойчивость

One or more changes within the HIV reverse transcriptase at amino acid positions 100, 103, 106, 108, 181, 188 and 190 are associated with resistance. These point mutations have also been implicated, either alone or in combination, in HIV resistance to other non-nucleoside reverse transcriptase inhibitors.

Общее описание

Nevirapine (Viramune) is more than 90% absorbed by theoral route and is widely distributed throughout the body. Itdistributes well into breast milk and crosses the placenta.Transplacental concentrations are about 50% those ofserum. The drug is extensively transformed by cytochromeP450 (CYP) to inactive hydroxylated metabolites; it mayundergo enterohepatic recycling.

Фармацевтические приложения

A synthetic heterocyclic compound formulated for oral use as anhydrous compound or as the hemihydrate in a liquid oral suspension.

Механизм действия

Nevirapine is a dipyridodiazepinone derivative that binds directly to RT . Thus, it blocks RNA- and DNA-dependent polymerase activities by causing a disruption of the enzyme's catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphate. The HIV-2 RT and human DNA polymerases are not inhibited by nevirapine. The 50% inhibitory concentration ranged within 10 to 100 nM against HIV-1.

Фармакокине?тика

Oral absorption: c. 93%
C_max 200 mg twice daily: c. 5.74 mg/L
C_min 200 mg twice daily: c. 2.88 mg/L
Plasma half-life: c. 36 h
Volume of distribution: c. 1.21 L/kg
Plasma protein binding: c. 60%
Absorption and distribution
Nevirapine is orally very well absorbed and widely distributed. CNS penetration is good and the semen:plasma ratio is in the range of 0.6–1. It is distributed into breast milk.
Metabolism and excretion
It is extensively metabolized by cytochrome P₄₅₀ enzymes into a number of hydroxylated intermediates that are subsequently conjugated with glucuronide. Around 81% of the dose is excreted in urine (<5% as unchanged compound) and 10% in feces. There is no significant change in the pharmacokinetics in renal impairment. It is contraindicated in patients with severe hepatic impairment; caution should be exercised in patients with moderate hepatic dysfunction.

Клиническое использование

Treatment of HIV-1 infection in adults and children over 2 months old (in combination with other antiretroviral therapies)
Reduction of maternal transmission of HIV to the fetus (recommended only for use in HIV-infected treatment-naive women in labor who have had no prior HIV therapy)

Побочные эффекты

Life-threatening hepatic events, including fulminant hepatitis, have been observed in treatment-naive patients, generally within the first few weeks of treatment, but sometimes later. Approximately half the patients also develop skin rash, with or without fever or constitutional symptoms. Women with elevated CD4 counts (>250 cells/mm³) appear to be at highest risk. Men with pretreatment CD4 counts >400 cells/mm³ are also at increased risk. These risks exist in the absence of underlying hepatic abnormalities and, in some cases, hepatic injury continues to progress despite discontinuation of treatment. Treatment should stop, and not be restarted, in patients with clinical evidence of hepatitis. A starting dose of 200 mg per day, with escalation to full dose if no adverse reaction occurs, reduces the frequency of reaction. Single doses given to mothers or infants for prevention of perinatal HIV infection appear safe.