Nevirapine (Page 6 of 9)

12.4 Microbiology

Mechanism of Action
Nevirapine is a 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 α, β, γ, or δ) are not inhibited by nevirapine.

Antiviral Activity
The antiviral activity of nevirapine has been measured in a variety 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 primarily (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) against clinical isolates of HIV-1 clades A, B, C, D, F, G, and H, and circulating recombinant forms CRF01_AE, CRF02_AG and CRF12_BF. 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 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.

Resistance
HIV-1 isolates with reduced susceptibility (100- to 250-fold) to nevirapine emerge in cell culture. Genotypic analysis showed mutations in the HIV-1 RT gene 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.

Phenotypic and genotypic changes in HIV-1 isolates from treatment-naïve subjects receiving either nevirapine (n=24) or nevirapine and zidovudine (n=14) were monitored in Phase 1 and 2 trials ranging from 1 to 12 weeks or longer. After 1 week of nevirapine monotherapy, isolates from 3/3 subjects had decreased susceptibility to nevirapine in cell culture. One or more of the RT mutations resulting in amino acid substitutions K103N, V106A, V108I, Y181C, Y188C, and G190A were detected in HIV-1 isolates from some subjects as early as 2 weeks after therapy initiation. By week eight of nevirapine monotherapy, 100% of the subjects tested (n=24) had HIV-1 isolates with a greater than 100-fold decrease in susceptibility to nevirapine in cell culture compared to baseline, and had one or more of the nevirapine-associated RT resistance substitutions. Nineteen of these subjects (80%) had isolates with Y181C substitutions regardless of dose.

Genotypic analysis of isolates from antiretroviral-naïve subjects experiencing virologic failure (n=71) receiving nevirapine once daily (n=25) or twice daily (n=46) in combination with lamivudine and stavudine (trial 2NN) for 48 weeks showed that isolates from 8/25 and 23/46 subjects, respectively, contained one or more of the following NNRTI resistance-associated substitutions: Y181C, K101E, G190A/S, K103N, V106A/M, V108I, Y188C/L, A98G, F227L, and M230L.

For trial 1100.1486, genotypic analysis was performed for baseline and on-therapy isolates from 23 and 34 subjects who experienced virologic failure in the nevirapine extended release tablets and immediate-release nevirapine tablets treatment group, respectively. Nevirapine resistance-associated substitutions developed in the on-therapy isolates of 78% (18/23) of the subjects who had virologic failures in the nevirapine extended release tablets treatment group and 88% (30/34) of the subjects in the immediate-release nevirapine tablets treatment group, respectively. The Y181C nevirapine resistance-associated substitution was found alone or in combination with other nevirapine resistance-associated substitutions (K101E, K103N, V106A, V108I, V179D/E/I, Y188 C/F/H/L/N, G190A, P225H, F227L, M230L) in isolates from 14 subjects failing nevirapine extended release tablets treatment and 25 subjects failing immediate-release nevirapine tablets treatment. On-therapy isolates from 1 subject in nevirapine extended release tablets treatment group developed a novel amino acid substitution Y181I and isolates from another subject in the immediate-release nevirapine tablets treatment group developed a novel amino acid substitution Y188N. Phenotypic analysis showed that Y188N and Y181I substitutions conferred 103- and 22-fold reductions in susceptibility to nevirapine, respectively

Cross-resistance
Rapid emergence of HIV-1 strains which are cross-resistant to NNRTIs has been observed in cell culture. Nevirapine-resistant HIV-1 isolates were cross-resistant to the NNRTIs delavirdine, efavirenz and etravirine. The Y188N conferred 22- and 7-fold reductions in susceptibility to delavirdine and efavirenz, respectively, but showed no decrease in susceptibility to etravirine. Similarly, the Y181I substitution reduced susceptibility to delavirdine and etravirine 3- and 8-fold, respectively, but did not reduce susceptibility to efavirenz. However, nevirapine-resistant isolates were susceptible to the NRTIs ddI and ZDV. Similarly, ZDV-resistant isolates were susceptible to nevirapine in cell culture.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
Long-term carcinogenicity studies in mice and rats were carried out with nevirapine. Mice were dosed with 0, 50, 375 or 750 mg/kg/day for two years. Hepatocellular adenomas and carcinomas were increased at all doses in males and at the two high doses in females. In studies in which rats were administered nevirapine at doses of 0, 3.5, 17.5 or 35 mg/kg/day for two years, an increase in hepatocellular adenomas was seen in males at all doses and in females at the high dose. The systemic exposure (based on AUCs) at all doses in the two animal studies was lower than that measured in humans at the 200 mg twice daily dose. The mechanism of the carcinogenic potential is unknown.

Mutagenesis
However, in genetic toxicology assays, nevirapine showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included microbial assays for gene mutation (Ames: Salmonella strains and E. coli), mammalian cell gene mutation assay (CHO/HGPRT), cytogenetic assays using a Chinese hamster ovary cell line and a mouse bone marrow micronucleus assay following oral administration. Given the lack of genotoxic activity of nevirapine, the relevance to humans of hepatocellular neoplasms in nevirapine-treated mice and rats is not known.

Impairment of Fertility In reproductive toxicology studies, evidence of impaired fertility was seen in female rats at doses providing systemic exposure, based on AUC, approximately equivalent to that provided with the recommended clinical dose of nevirapine.

13.2 Animal Toxicology and/or Pharmacology

Animal studies have shown that nevirapine is widely distributed to nearly all tissues and readily crosses the blood-brain barrier.

14 CLINICAL STUDIES

14.1 Adult Patients

Trial BI 1090 was a placebo-controlled, double-blind, randomized trial in 2249 HIV-1 infected subjects with less than 200 CD4+ cells/mm3 at screening. Initiated in 1995, BI 1090 compared treatment with nevirapine + lamivudine + background therapy versus lamivudine + background therapy in NNRTI-naïve subjects. Treatment doses were nevirapine, 200 mg daily for two weeks followed by 200 mg twice daily or placebo, and lamivudine, 150 mg twice daily. Other antiretroviral agents were given at approved doses. Initial background therapy (in addition to lamivudine) was one NRTI in 1309 subjects (58%), two or more NRTIs in 771 (34%), and PIs and NRTIs in 169 (8%). The subjects (median age 36.5 years, 70% Caucasian, 79% male) had advanced HIV-1 infection, with a median baseline CD4+ cell count of 96 cells/mm3 and a baseline HIV-1 RNA of 4.58 log10 copies/mL (38,291 copies/mL). Prior to entering the trial, 45% had previously experienced an AIDS-defining clinical event. Eighty-nine percent had antiretroviral treatment prior to entering the trial. BI 1090 was originally designed as a clinical endpoint trial. Prior to unblinding the trial, the primary endpoint was changed to proportion of subjects with HIV-1 RNA less than 50 copies/mL and not previously failed at 48 weeks. Treatment response and outcomes are shown in Table 5.

Table 5 BI 1090 Outcomes Through 48 Weeks
Outcome Nevirapine (N=1121)% Placebo (N=1128)%
Responders at 48 weeks: HIV-1 RNA <50 copies/mL 18 2
Treatment Failure 82 98
Never suppressed viral load 45 66
Virologic failure after response 7 4
CDC category C event or death 10 11
Added antiretroviral therapy1 while <50 copies/mL 5 1
Discontinued trial therapy due to AE 7 6
Discontinued trial <48 weeks2 9 10
1 including change to open-label nevirapine 2 includes withdrawal of consent, lost to follow-up, non-compliance with protocol, other administrative reasons

The change from baseline in CD4+ cell count through one year of therapy was significantly greater for the nevirapine group compared to the placebo group for the overall trial population (64 cells/mm3 vs 22 cells/mm3 , respectively), as well as for subjects who entered the trial as treatment-naïve or having received only ZDV (85 cells/mm3 vs 25 cells/mm3 , respectively).

At two years into the trial, 16% of subjects on nevirapine had experienced class C CDC events as compared to 21% of subjects on the control arm.

Trial BI 1046 (INCAS) was a double-blind, placebo-controlled, randomized, three-arm trial with 151 HIV-1 infected subjects with CD4+ cell counts of 200 to 600 cells/mm3 at baseline. BI 1046 compared treatment with nevirapine +zidovudine+didanosine to nevirapine +zidovudine and zidovudine+didanosine. Treatment doses were nevirapine at 200 mg daily for two weeks followed by 200 mg twice daily or placebo, zidovudine at 200 mg three times daily, and didanosine at 125 or 200 mg twice daily (depending on body weight). The subjects had mean baseline HIV-1 RNA of 4.41 log10 copies/mL (25,704 copies/mL) and mean baseline CD4+ cell count of 376 cells/mm3. The primary endpoint was the proportion of subjects with HIV-1 RNA less than 400 copies/mL and not previously failed at 48 weeks. The virologic responder rates at 48 weeks were 45% for subjects treated with nevirapine +zidovudine+didanosine, 19% for subjects treated with zidovudine+didanosine, and 0% for subjects treated with nevirapine +zidovudine.

CD4+ cell counts in the nevirapine +ZDV+ddI group increased above baseline by a mean of 139 cells/mm3 at one year, significantly greater than the increase of 87 cells/mm3 in the ZDV+ddI subjects. The nevirapine +ZDV group mean decreased by 6 cells/mm3 below baseline.

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