Composition And Formulation Of Nevirapine Biology Essay


Nevirapine is one of the oldest antiretroviral drugs that has been used for treating HIV infections and is still used commonly. With more than 1 million patient-years of accumulated experience worldwide, a large data set has been produce, providing an increased knowledge of this nonnucleoside reverse transcriptase inhibitor (NNRTI). Nevirapine is among the most extensively used antiretroviral drugs in Africa and Asia, giving it a prominent role in the global effort to control HIV infection (1).It is also on the New Zealand market (2). It is also known by the name Virumune, the brand name (3).

1.Composition and formulation of Nevirapine:

Figure : chemical structure of nevirapine (5)Nevirapine is structurally a member of the dipyridodiazepinone chemical class of compounds (3). The chemical name of nevirapine is 1 l-cyclopropyl-5,1 l-dihydro-4-methyl-6H-dipyrido [3,2-b:2',3'-e][l,4] diazepin-6-one. Nevirapine is a white to off-white crystalline powder with the molecular weight of 266.30 and the molecular formula C15H14N4O (3). Nevirapine is a non-nucleoside reverse transcriptase inhibitor (nNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases alpha, beta, or sigma) are not inhibited by nevirapine. Nevirapine is, in general, simply prescribed after the immune system has declined and infections have become apparent. It is at all times, taken with at least one other HIV medication for instance Retrovir or Videx. The virus can acquire resistance to nevirapine if the drug is taken by itself, even though if used correctly, nevirapine is effective for only a limited time (4) (5). Nevirapine is taken as a tablet as well an oral suspension. It has been patients taking this drug are strongly advised to never take more than one form of nevirapine at the same time. Nevirapine administration is not affected in the absence or presence food, antacid, or didanosine (4). Each tablet contains 200 mg of nevirapine and the inactive ingredients microcrystalline cellulose, lactose monohydrate, povidone, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate (3). Viramune is the oral suspension form and contains 10mg of nevirapine per mL. Just like the tablet form the colour is white to off-white (3) (4). Thumb

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2. The pharmacokinetics of Nevirapine

In regard to different pharmacokinetic behaviour based on gender difference, a multinational 2NN trial was carried out, where a population pharmacokinetic substudy of 1077 subjects was performed that included 391 females. Female subjects showed a 13.8% lower clearance of nevirapine than did men. Since neither body weight nor Body Mass Index (BMI) had an influence on the clearance of nevirapine, the effect of gender cannot solely be explained by body size (3). An evaluation was taken to see if there was a significant difference on the effect of the drug based on the race of the patient. Nevirapine plasma concentrations (pooled data from several clinical trials) from HIV-1-infected subjects (27 Black, 24 Hispanic, 189 Caucasian) revealed no marked difference in nevirapine steady-state trough concentrations (median Cminss = 4.7 mcg/mL Black, 3.8 mcg/mL Hispanic, 4.3 mcg/mL Caucasian) with long-term nevirapine treatment at 400 mg/day. Though, the pharmacokinetics of nevirapine have not been assessed exclusively for the effects of ethnicity (3).

2.1) Absorption and distribution (bioavailability)

Nevirapine is promptly absorbed (>90%) following oral administration in healthy volunteers and in adults with HIV-1 infection (6). Absolute bioavailability in 12 healthy adults following single-dose administration was 93 ± 9% for a 50 mg tablet and 91 ± 8% for an oral solution. Peak plasma nevirapine concentrations of 2 ± 0.4 mcg/ml (7.5 mcM) were attained by 4 hours following a single 200 mg dose (4)(6). Following numerous doses, nevirapine peak concentrations seem to increase linearly in the dose range of 200 to 400 mg/day (6). Steady state through nevirapine concentrations of 4.5 ± 1.9 mcg/ml (17 ± 7 mcM), (n = 242) were attained at 400 mg/day. The absorption of nevirapine is not affected by food, antacids or medicinal products that are prepared with an alkaline buffering agent (4) (5) (6). The distribution of nevirapine is exceedingly lipophilic and is in effect non-ionized at physiologic pH. Animal studies have revealed that nevirapine is extensively distributed to just about all tissues and effortlessly crosses the blood-brain barrier (6). Following administration in healthy adults, the apparent volume of distribution (Vdss) of nevirapine was 1.21 ± 0.09 l/kg, signifying that nevirapine is also widely distributed in humans. Nevirapine readily crosses the placenta and is appears in breast milk. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1-10 mcg/ml. Nevirapine concentrations in human cerebrospinal fluid (n=6) were 45% (± 5%) of the concentrations in plasma; this proportion is roughly equivalent to the portion not bound to plasma protein (6).

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2.2) Elimination (Metabolism and Excretion)

In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is significantly biotransformed by the use of cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes proposes that oxidative metabolism of nevirapine is mediated predominantly by cytochrome P450 isoenzymes from the CYP3A family, even though other isoenzymes may possess a secondary role (6) . In a mass balance/excretion study in eight healthy male volunteers dosed to steady state with nevirapine 200 mg twice daily followed by a single 50 mg dose of 14C-nevirapine, more or less 91.4% ± 10.5% of the radiolabelled dose was recovered, with urine (81.3% ± 11.1%) indicating the main route of excretion compared to faeces (10.1% ± 1.5%) (6). More than 80% of the radioactivity in urine was made up of glucuronide conjugates of hydroxylated metabolites. Thus cytochrome P450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine biotransformation and elimination in humans. Only a small portion (<5%) of the radioactivity in urine (representing <3% of the entire dose) was made up of parent compound; as a result, renal excretion of nevirapine plays a small role in elimination of the parent compound (6)

3) Mechanisms of action/Therapeutic Application:

Nevirapine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus-1 (HIV-1) (4) (5). Nevirapine binds completely to reverse transcriptase (RT) and obstruct RNA-dependent and DNA-dependent polymerase activities by initiating interference of the enzyme's catalytic site (4). The activity of nevirapine does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases are not hindered by nevirapine (4).

3.1) Therapeutic applications:

The antiviral activity of nevirapine has been evaluated in a range of cell lines including peripheral blood mononuclear cells, monocyte-derived macrophages, and lymphoblastoid cell lines. In an assay using human embryonic kidney 293 cells, the median EC50 value (50% inhibitory concentration) of nevirapine was 90 nM against a panel of 2923 isolates of HIV-1 that were mostly (93%) clade B clinical isolates from the United States. The 99th percentile EC50 value was 470 nM in this trial. The median EC50 value was 63 nM (range 14 to 302 nM, n=29) (7). Nevirapine in combination with efavirenz exhibited strong antagonistic anti-HIV-1 activity in cell culture and was additive to antagonistic with the protease inhibitor ritonavir or the fusion inhibitor enfuvirtide. Nevirapine exhibited additive to synergistic anti-HIV-1 activity in combination with the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and tipranavir, and the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine. The anti-HIV-1 activity of nevirapine was antagonized by the anti-HBV drug adefovir and by the anti-HCV drug ribavirin in cell culture (7)

4. Adverse effects/ contraindications/drug interactions:

4.1) Adverse effects:



Stevens-Johnson syndrome, Toxic epidermal necrolysis


Granulocytopenic disorder, Neutropenia




Allergic reaction to drug, Anaphylaxis, Immune hypersensitivity reaction



Rash (very common); severe skin reactions (common); elevated Blood Pressure;; hepatitis; jaundice; immune reactivation syndrome; fever; headache; GI upset; fatigue; myalgia; angioedema; anaphylaxis; blood dyscrasias;) anaemia (especially in children) Rare adverse effects include arthralgia, rhabdomyolysis and others (8)

4.2) contraindications:

Nevirapine oral suspension is contraindicated in patients with moderate or severe hepatic impairment (4).It is also contraindicated for use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens (3).

4.3) drug interactions:




Concurrent use of NEVIRAPINE and ST JOHN'S WORT may result in decreased nevirapine concentrations and an increased risk of antiretroviral resistance and treatment failure.

NEVIRAPINE [Systemic] -- EFAVIRENZ [Systemic]



Concurrent use of EFAVIRENZ and NEVIRAPINE may result in decreased efavirenz plasma concentrations and increased adverse events.




Concurrent use of ATAZANAVIR and NEVIRAPINE may result in increased risk of virologic failure due to decreased atazanavir bioavailability; increased risk of nevirapine toxicity due to increased nevirapine bioavailability.

ARTEMETHER [Systemic] -- NEVIRAPINE [Systemic]



Concurrent use of ARTEMETHER/LUMEFANTRINE and NEVIRAPINE may result in decreased artemether and dihydroartemisinin concentrations.

ITRACONAZOLE [Systemic] -- NEVIRAPINE [Systemic]



Concurrent use of ITRACONAZOLE and NEVIRAPINE may result in decreased itraconazole bioavailability.

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RIFAMPIN [Systemic] -- NEVIRAPINE [Systemic]



Concurrent use of NEVIRAPINE and RIFAMPIN may result in decreased nevirapine serum concentrations and possible loss of nevirapine efficacy.

(table from (4), (7)

5. Funding and marketing issues:

Generic antiretroviral drug for treating HIV infection is approved from the Food and Drug Administration. Mylan (a drug producing company) publicised the approval of nevirapine tablets in the 200-mg strength. The drug is a generic version of Boehringer Ingelheim's Viramune. Mylan began shipping the drug without delay after approval. Various versions of the drug had sales of $116.6 million during the 12-month period ended in March, according to IMS Health. (9) On May 22, 2012, FDA permitted ten generic product applications for nevirapine tablets USP, 200 mg (10). In addition, one generic approval was granted for an oral suspension formulation USP 50 mg/mL, made by Aurobindo Pharma Limited. These products are generic versions of the Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), Viramune, made by Boehringer Ingelheim. The approvals mean that these generic nevirapine formulations can be marketed in the United States. (10)In New Zealand, nevirapine is readily available in tablet form of 200mg and in oral suspension form of 10mg/mL. Both types of the drug are fully subsidised (2). The tablet form comes in a bottle containing 60 tablets at a cost of around $319.80 (2). There are no serious cases for nevirapine overdosage. Cases of nevirapine overdose at doses ranging from 800 to 1800 mg per day for up to 15 days have been reported. Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting, and weight decrease. All events improve following discontinuation of nevirapine (7).

PART B: Thoughts on consuming nevirapine:

Nevirapine, an antiviral drug aiding the disease of HIV aids is an important drug. It has its advantages and disadvantages, like all other drugs on the market. However the benefits of taking nevirapine outweigh the disadvantages. There are other drugs with the same properties, that are available on the New Zealand market, such as efavirenz (available in 50mg, 200mg, 600mg tablets) and Etravirine (12). The disadvantage of nevirapine is that it comes in a smaller range of doses (2). Whereas an advantage of nevirapine is that it can be taken regardless of whether one has eaten or not, does not have as many dangerous drug interactions as efavirenz (11).