Nevirapine

Description

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.

Chemical Properties

Crystalline Solid

Originator

Neve,Le Sante,India

Uses

amyloidosis therapy

Uses

A potent (IC50=84nM) and selective non-nucleoside inhibitorf HIV-1 reverse transcriptase

Uses

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.

Definition

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.

Indications

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.

Manufacturing Process

There are 3 ways for preparing of nevirapine.
117.5 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide, 23.3 kg of calcium oxide and 59.4 kg of cyclopropylamine (molar ratio: 1:1:2.5) are heated to between 135° and 145°C in 235 L of diglyme (diethylene glycoldimethylether) in a 500 L VA autoclave over a period of 6 to 8 hours. The reaction mixture is then cooled to a temperature of 20°-30°C and filtered. The filter cake is washed with 58.8 L of diglyme. The filtrates are combined and initially 200 L of solvent is distilled off. The residue is then diluted with a further 117.5 L of diglyme. The resultant diluted solution is added over a period of 20 to 40 minutes to a suspension of 45.0 kg of 60% sodium hydride in 352.5 L of diglyme, heated to 130°C. The storage vessel and conduits are rinsed with a further 55.8 L of diglyme, and the mixture is stirred at a temperature of between 130° and 140°C for a further 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 470 L of water. After cooling to a temperature of about 25°C, 235.0 L of cyclohexane and 57.11 of glacial acetic acid are added to the reaction mixture. The mixture is then stirred for about 1 hour at temperature of 10° to 25°C. The resultant suspension is centrifuged and the centrifuged material is then washed with 235.0 L of methyl-tertbutylether and subsequently with 353.5 L of water and finally with 235 L of ethanol. In this way, after drying, 92.5 kg (83.5% of theory) of 11- cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6- one (nevirapine) is isolated.
117.5 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide, 46.7 kg of calcium oxide and 47.5 kg of cyclopropylamine (molar ratio: 1:2:2) are heated to 135° to 145°C in 235 L of diglyme (diethylene glycol dimethylether) in a 500 L VA autoclave over a period of 6 to 8 hours. The reaction mixture is then cooled to a temperature of 20° to 30°C and filtered. The filter cake is washed with 58.8 L of diglyme. The filtrates are combined and about 188 L of solvent is distilled off. The residue is then diluted with a further 117.5 L of diglyme. Over a period of 20 to 40 minutes, the resultant diluted solution is added to a suspension of 45.0 kg of 60% sodium hydride in 352.5 L of diglyme, heated to 130°C. The storage vessel and conduits are rinsed with a further 55.8 L of diglyme and the mixture is stirred at a temperature of 130° to 140°C for a further 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 470.0 L of water. The reaction mixture is cooled to a temperature of about 25°C and 235.0 L of cyclohexane and 57.1 L of glacial acetic acid are added. The mixture is then stirred for about 1 hour at a temperature of 10o to 25°C. The resultant suspension is centrifuged and the centrifuged material is washed with 235.0 L of methyl tert-butylether, followed by 353.5 L of water and finally with 235 L of ethanol. In this way, after drying, 90.6 kg (81.7% of theory) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido-[3,2-b:2',3'- e][1,4]diazepin-6-one (nevirapine) is isolated.
287.2 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide, 57.0 kg of calcium oxide and 87.1 kg of cyclopropylamine (molar ratio: 1:1:1.5) are heated in 574 L of diglyme (diethylene glycol-dimethylether) to 135°-145°C for about 30 minutes in a 1200 L VA stirring apparatus. This produces a pressure of 1.2-1.5 bar and about 50% of the starting material is reacted. To this mixture, over about 30 minutes at 135°-145°C, a further 58.1 kg of cyclopropylamine is added producing a pressure of 3.0-3.5 bar, and another 25% of the starting material is reacted. The mixture is then kept at 135°-145°C for a period of 5 to 6 hours. The reaction mixture is then cooled to a temperature of 20° to 30°C and filtered. The filter cake is washed with 144 L of diglyme. The filtrates are combined and 400 L of solvent is distilled off. The residue is then diluted with a further 287 L of diglyme. Over 20-40 minutes, the resultant diluted solution is added to a suspension of 110 kg of 60% sodium hydride in 862 L of diglyme, heated to 130°C. The storage vessel and conduits are rinsed with a further 144 L of diglyme and the mixture is stirred at a temperature of 130° to 140°C for another 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 1150 L of water. After the reaction mixture has been cooled to a temperature of about 25°C, 575 L of cyclohexane and 147 L of glacial acetic acid are added. The mixture is then stirred for about 1 hour at a temperature of 10°-25°C. The resultant suspension is centrifuged and the centrifuged material is then washed with 575 L of methyl-tert-butylether, followed by 862 L of water and finally with 575 L of ethanol. In this way, after drying, 225 kg (83.0% of theory) of 11-cyclopropyl-5,11-dihydro-4-methyl- 6H-dipyrido[3,2-b :2',3'-e][1,4 ]diazepin-6-one (nevirapine) is obtained.

brand name

Viramune (Boehringer Ingelheim);Nevimune.

Therapeutic Function

Antiviral

Acquired resistance

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.

General Description

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.

Pharmaceutical Applications

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

Biochem/physiol Actions

Nevirapine is an allosteric, non-nucleoside inhibitor of HIV reverse transcriptase (NNRTI). The Ki for inhibition of wild-type RT by Nevirapine is 200 nM.

Mechanism of action

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.

Pharmacokinetics

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.

Clinical Use

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)

Side effects

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.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: reduces concentration of clarithromycin, but concentration of active metabolite increased, also concentration of nevirapine increased; concentration decreased by rifampicin - avoid; possibly increased rifabutin concentration.
Anticoagulants: may increase or reduce effect of warfarin.
Antidepressants: concentration reduced by St John’s wort - avoid.
Antifungals: concentration of ketoconazole reduced - avoid; concentration increased by fluconazole; possibly reduced caspofungin and itraconazole concentration - may need to increase caspofungin and itraconazole dose.
Antipsychotics: possibly reduced aripiprazole concentration - increase aripiprazole dose.
Antivirals: concentration of dolutegravir, indinavir and efavirenz reduced and possibly etravirine, fosamprenavir, lopinavir, simeprevir and atazanavir - avoid with atazanavir, etravirine and simeprevir consider increasing lopinavir dose; increased risk of granulocytopenia with zidovudine.
Cytotoxics: avoid with olaparib.
Guanfacine: concentration possibly reduced - increase guanfacine dose.
Oestrogens and progestogens: accelerated metabolism (reduced contraceptive effect).
Orlistat: absorption possibly reduced by orlistat.
Ulipristal: possibly reduces contraceptive effect.

Metabolism

Nevirapine is extensively metabolised by hepatic microsomal enzymes, mainly by the cytochrome P450 isoenzymes CYP3A4 and CYP2B6, to several inactive hydroxylated metabolites. Auto-induction of these enzymes results in a 1.5- to 2-fold increase in apparent oral clearance after 2-4 weeks at usual dosage, and a decrease in terminal half-life. Nevirapine is mainly excreted in the urine as glucuronide conjugates of the hydroxylated metabolites.