ANTIRETROVIRAL DRUGS

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DESCRIPTION
Lamivudine, Nevirapine and Stavudine tablets are for oral administration. Each tablet contains 150mg of lamivudine USP, 200mg of nevirapine USP and 30mg of stavudine USP. In addition, each tablet contains the following inactive ingredients: lactose monohydrate, corn starch, croscarmellose sodium, FD&C yellow # 6 / sunset yellow FCF AL, povidone, isopropyl alcohol, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate.
Lamivudine (also known as 3TC) is a synthetic nucleoside analogue with activity against HIV-1 and HBV. The chemical name of lamivudine is (-) 2',3'-dideoxy,3'-thiacytidine. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3. Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70mg/mL in water at 20 degrees C.

Nevirapine is non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Nevirapine is structurally a member of the dipyridodiazepinone chemical class of compounds. The chemical name of nevirapine is 11-cyclopropyl-5, 11-dihydro-4-methyl-6H-dipyrido [3,2-b:2',3'-e][1,4] diazepin-6-one. Nevirapine is a white to off-white crystalline powder with the molecular weight of 266.30 and the molecular formula C15H14N4O.
Stavudine (d4T) is a sythetic thymidine nucleoside analogue, active against the human immunodeficiency virus (HIV). The chemical name for stavudine is 2',3'-didehydro-3'-deoxythymidine. Stavudine is a white to off-white crystalline solid with the molecular formula C10H12N2O4 and a molecular weight of 224.2. The solubility of stavudine at 23 degrees C is approximately 83 mg/mL in water and 30mg/mL in propylene glycol. The non-octanol/water portion coefficient of stavudine at 23 degrees C is 0.144.

MICROBIOLOGY
Mechanism of Action:
Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is the inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue into viral DNA. 3TC-TP is a weak inhibitor of mammalian DNA polymerases.
Nevirapine is non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases) are not inhibited by nevirapine.
Stavudine, a nucleoside analogue of thymidine, is phosphorylated by cellular kinases to the active metabolite stavudine triphosphate. Stavudine triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) by competing with the natural substrate thymidine triphosphate and by causing DNA chain termination following its incorporation into viral DNA. Stavudine triphosphate inhibits cellular DNA polymerases and markedly reduces the synthesis of mitochondrial DNA.

Antiviral Activity:
Lamivudine - The cell culture antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes) using standard susceptibility assays. In HIV-1-infected MT-4 cells, lamivudine in combination with zidovudine at various ratios exhibited synergistic antiretroviral activity.
Nevirapine - The antiviaral activity of nevirapine has been measured in a variety of cell lines including peripheral blood mononuclear cells, monocyte derived macrophages, and lymphoblastoid cell lines. Nevirapine had no antiviral activity in cell culture against group O HIV-1 isolates (n=3) or HIV-2 isolates (n=3) replicating in cord blood mononuclear cells. 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 ant-HIV-1 activity in combination with the protease inhbitors: 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.
Stavudine - The cell culture antiviral activity of stavudine was measured in peripheral blood mononuclear cells,monocytic cells, and lymphoblastoid cell lines. In cell culture, stavudine exhibited additive to antagonistic anti-HIV-1 activity in combination with zidovudine. Stavudine in combination with either abacavir, didanisine, or tenofovir exhibited additive to synergistic anti-HIV-1 activity. The relationship between cell culture susceptibilty of HIV-1 to stavudine and the inhibition of HIV-1 replication in humans has not been establshed.

Resistance:
Lamivudine - Lamivudine-resistant variants of HIV-1 have been selected in cell culture. Genotypic analysis showed that the resistance was due to a specific amino acid substitution in the HIV-1 reverse transcriptanse at codon 184 changing the methionine to either isoleucine or valine (184V/I).

Nevirapine - HIV-1 isolates with reduced susceptibility to nevirapine emerge in cell culture. Genotypic analysis showed mutations in the HIV-1 RT encoding Y181C and/or V106A substitutions depending upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in cell culture was not altered when selection included nevirapine in combination with several other NNRTIs.

Stavudine - HIV-1 isolates with reduced susceptibility to stavudine have been selected in cell in cell culture (strain specific) and and were
also obtained from patients treated with stavudine.

Cross - Resistance:
Lamivudine - lamivudine resistant HIV-1 mutants were cross - resistant to didanosine (ddl). In some patients treated with zidovudine (ZDV) plus didanosine, isolates resistant to multiple reverse transcriptanse inhibitors, including lamivudine have emerged.
Nevirapine - Rapid emergence of HIV-1 strains which are cross- resistant to NNRTs has been observed in cell culture. Nevirapine - resistant isolates were susceptible to the NNRTs, ddl and ZDV. Similarly, ZDV - resistant isolates were susceptible to nevirapine in cell culture.
Stavudine - Cross-resistance among HIV-1 reverse transciptase inhibitors has been observed. Several studies have demonstrated that prolonged stavudine treatment can selct and/ or maintain mutations associated zith zidovudine resistance.

CLINICAL PHARMACOLOGY

Pharmacokinetics in Adults:
The rate and extent of absoption of Lamivudine, Nevirapine and Stavudine from the combined tablets ( 150 mg / 200 mg / 30 mg ) were bioequivalent to that of Epivir tablets, Zerit capsules and Viramune tablets respectively, when administered to healthy volunteers in the fasted state.

Lamivudine:
Absorption and Bioavailability - Lamivudine was rapidly absorbed after oral administration in HIV - infected patients. The cumulation ratio of lamivudine in HIV-1 positive asymptomatic adults with normal renal function was 1.5 following 15 days of oral administration of 2 mg/kg twice daily.
Distribution - According to studies, lamivudine distributes into extravascular spaces. The volume of distribution is independent of dose and did not correlate with body weight. Binding of lamivudine to human plasma is low (<36%)). Metabolism - Metabolism of lamivudine is minor route of elimination. In man, the only known metabolite of lumivudine is the trans-sulfoxide metabolite. Serum concentrations of this metabolite have not been determined . Elimination - The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. Nevirapine:: Absorption and Bioavailability - Nevirapine is readily absorbed (>90%) after oral administration in healthy volunteers and in adults with HIV-1 infection.
Distribution - Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. Nevirapine is widely distributed in humans. It readily crosses the placenta and is also found in breast milk.
Metabolism/Elimination - In vivo in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytocrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytocrome P450 (CYP) isozymes from the CYP3A and CYP2B6 families, although other isozymes may have a secondary role.
Stavudine::
Absorption and Bioavailability - Following oral administration, stavudine is rapidly absorbed is rapidly absorbed, with peak plasma occuring within 1 hour after dosing.
Distribution - Stavudine distributes equally between red cells and plasma.
Metabolism - Metabolism plays a limited role in the clearance of stavudine.
Elimination - In HIV-infected patients, renal elimination of unchanged drug accounts for about 40% of the overall clearance regardless of the route of administration.

Effects of Food on Absorption of Lamivudine, Nevirapine and Stavudine - The extent of lamivudine, nevirapine and stavudine absorption following administration has not been evaluated. Therefore, Lamivudine, Nevirapine & Stavudine tablets 150mg/200mg/30mg should be taken under fasting conditions.