CLINICAL PHARMACOLOGY
Mechanism of Action
Nevirapine is an antiviral drug [see Microbiology ].
Pharmacokinetics
Adults
Absorption
and Bioavailability
Nevirapine is readily absorbed (greater than 90%) after oral administration
in healthy volunteers and in adults with HIV-1 infection. Absolute
bioavailability in 12 healthy adults following single-dose administration
was 93 ± 9% (mean ± SD) for a 50 mg tablet and 91 ± 8% for an oral
solution. Peak plasma nevirapine concentrations of 2 ± 0.4 mcg/mL
(7.5 micromolar) were attained by 4 hours following a single 200 mg
dose. Following multiple doses, nevirapine peak concentrations appear
to increase linearly in the dose range of 200 to 400 mg/day. Steady-state
trough nevirapine concentrations of 4.5 ± 1.9 mcg/mL (17 ± 7 micromolar),
(n=242) were attained at 400 mg per day. Nevirapine tablets and suspension
have been shown to be comparably bioavailable and interchangeable
at doses up to 200 mg. When VIRAMUNE (200 mg) was administered to
24 healthy adults (12 female, 12 male), with either a high-fat breakfast
(857 kcal, 50 g fat, 53% of calories from fat) or antacid (Maalox® 30 mL), the extent of nevirapine absorption (AUC)
was comparable to that observed under fasting conditions. In a separate
trial in HIV-1 infected subjects (n=6), nevirapine steady-state systemic
exposure (AUCτ) was not significantly altered
by didanosine, which is formulated with an alkaline buffering agent.
VIRAMUNE may be administered with or without food, antacid or didanosine.
Distribution
Nevirapine is highly lipophilic and is essentially
nonionized at physiologic pH. Following intravenous administration
to healthy adults, the apparent volume of distribution (Vdss) of nevirapine
was 1.21 ± 0.09 L/kg, suggesting that nevirapine is widely distributed
in humans. Nevirapine readily crosses the placenta and is also found
in breast milk [see Use in Specific Populations ]. Nevirapine is about 60%
bound to plasma proteins in the plasma concentration range of 1-10
mcg per mL. Nevirapine concentrations in human cerebrospinal fluid
(n=6) were 45% (±5%) of the concentrations in plasma; this ratio is
approximately equal to the fraction not bound to plasma protein.
Metabolism/Elimination
In vivo trials in humans
and in vitro studies with human liver microsomes
have shown that nevirapine is extensively biotransformed via cytochrome
P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that
oxidative metabolism of nevirapine is mediated primarily by cytochrome
P450 (CYP) isozymes from the CYP3A and CYP2B6 families, although other
isozymes may have a secondary role. In a mass balance/excretion trial
in eight healthy male volunteers dosed to steady state with nevirapine
200 mg given twice daily followed by a single 50 mg dose of 14C-nevirapine, approximately 91.4 ± 10.5% of the radiolabeled
dose was recovered, with urine (81.3 ± 11.1%) representing the primary
route of excretion compared to feces (10.1 ± 1.5%). Greater 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 fraction (less than 5%) of the radioactivity
in urine (representing less than 3% of the total dose) was made up
of parent compound; therefore, renal excretion plays a minor role
in elimination of the parent compound.
Nevirapine is an inducer of hepatic cytochrome P450
(CYP) metabolic enzymes 3A and 2B6. Nevirapine induces CYP3A and CYP2B6
by approximately 20-25%, as indicated by erythromycin breath test
results and urine metabolites. Autoinduction of CYP3A and CYP2B6 mediated
metabolism leads to an approximately 1.5- to 2-fold increase in the
apparent oral clearance of nevirapine as treatment continues from
a single dose to two-to-four weeks of dosing with 200-400 mg per day.
Autoinduction also results in a corresponding decrease in the terminal
phase half-life of nevirapine in plasma, from approximately 45 hours
(single dose) to approximately 25-30 hours following multiple dosing
with 200-400 mg per day.
SpecificPopulations
Renal Impairment
HIV-1 seronegative adults with mild (CrCL
50-79 mL per min; n=7), moderate (CrCL 30-49 mL per min; n=6), or
severe (CrCL less than 30 mL per min; n=4) renal impairment received
a single 200 mg dose of nevirapine in a pharmacokinetic trial. These
subjects did not require dialysis. The trial included six additional
subjects with renal failure requiring dialysis.
In subjects with renal impairment (mild, moderate or
severe), there were no significant changes in the pharmacokinetics
of nevirapine. However, subjects requiring dialysis exhibited a 44%
reduction in nevirapine AUC over a one-week exposure period. There
was also evidence of accumulation of nevirapine hydroxy-metabolites
in plasma in subjects requiring dialysis. An additional 200 mg dose
following each dialysis treatment is indicated [see Dosage
and Administration and Use in
Specific Populations ].
Hepatic Impairment
In a steady-state trial comparing 46 subjects
with mild (n=17; expansion of some portal areas; Ishak Score 1-2),
moderate (n=20; expansion of most portal areas with occasional portal-to-portal
and portal-to-central bridging; Ishak Score 3-4), or severe (n=9;
marked bridging with occasional cirrhosis without decompensation indicating
Child-Pugh A; Ishak Score 5-6) fibrosis as a measure of hepatic impairment,
the multiple dose pharmacokinetic disposition of nevirapine and its
five oxidative metabolites were not altered. However, approximately
15% of these subjects with hepatic fibrosis had nevirapine trough
concentrations above 9,000 mcg per mL (2-fold the usual mean trough).
Therefore, patients with hepatic impairment should be monitored carefully
for evidence of drug-induced toxicity [see Warnings and Precautions ]. The subjects studied were
receiving antiretroviral therapy containing VIRAMUNE 200 mg twice
daily for at least 6 weeks prior to pharmacokinetic sampling, with
a median duration of therapy of 3.4 years.
In a pharmacokinetic trial where HIV-1 negative cirrhotic
subjects with mild (Child-Pugh A; n=6) or moderate (Child-Pugh B;
n=4) hepatic impairment received a single 200 mg dose of nevirapine,
a significant increase in the AUC of nevirapine was observed in one
subject with Child-Pugh B and ascites suggesting that patients with
worsening hepatic function and ascites may be at risk of accumulating
nevirapine in the systemic circulation. Because nevirapine induces
its own metabolism with multiple dosing, this single-dose trial may
not reflect the impact of hepatic impairment on multiple-dose pharmacokinetics.
Do not administer nevirapine to patients
with moderate or severe (Child-Pugh Class B or C, respectively) hepatic
impairment [see Contraindications (4), Warnings and Precautions ,
and Use in Specific Populations ].
Gender
In the multinational 2NN trial, 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.
Race
An evaluation of 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 per day.
However, the pharmacokinetics of nevirapine have not been evaluated
specifically for the effects of ethnicity.
Black subjects (n=80/group) in Trial 1100.1486 showed
approximately 30% to 35% higher trough concentrations than Caucasian
subjects (250-325 subjects/group) in both immediate-release VIRAMUNE
and VIRAMUNE XR treatment groups over 96 weeks of treatment at 400
mg per day.
Geriatric Subjects
Nevirapine pharmacokinetics in HIV-1-infected
adults do not appear to change with age (range 18–68 years); however,
nevirapine has not been extensively evaluated in subjects beyond the
age of 55 years [see Use in Specific Populations ].
Pediatric Subjects
Pharmacokinetic data for nevirapine have
been derived from two sources: a 48-week pediatric trial in South
Africa (BI Trial 1100.1368) involving 123 HIV-1 positive, antiretroviral-naïve
subjects aged 3 months to 16 years; and a consolidated analysis of
five Pediatric AIDS Clinical Trials Group (PACTG) protocols comprising
495 subjects aged 14 days to 19 years.
BI Trial 1100.1368 studied the safety, efficacy, and
pharmacokinetics of a weight-based and a body surface area (BSA)-based
dosing regimen of nevirapine. In the weight-based regimen, pediatric
subjects up to 8 years of age received a dose of 4 mg/kg once daily
for two weeks followed by 7 mg per kg twice daily thereafter. Subjects
8 years and older were dosed 4 mg/kg once daily for two weeks followed
by 4 mg/kg twice daily thereafter. In the BSA regimen, all pediatric
subjects received 150 mg/m2 once daily
for two weeks followed by 150 mg/m2 twice
daily thereafter [see Use in Specific Populations and Adverse Reactions ]. Dosing of nevirapine at
150 mg/m2 BID (after a two-week lead-in
of 150 mg/m2 QD) produced geometric mean
or mean trough nevirapine concentrations between 4-6 mcg per mL (as
targeted from adult data). In addition, the observed trough nevirapine
concentrations were comparable between the two dosing regimens studied
(BSA- and weight-based methods).
The consolidated analysis of Pediatric AIDS Clinical Trials Group
(PACTG) protocols 245, 356, 366, 377, and 403 allowed for the evaluation
of pediatric subjects less than 3 months of age (n=17). The plasma
nevirapine concentrations observed were within the range observed
in adults and the remainder of the pediatric population, but were
more variable between subjects, particularly in the second month of
age. For dose recommendations for pediatric patients [see
Dosage and Administration ].
Drug Interactions [see Drug
Interactions (7) ]
Nevirapine induces hepatic cytochrome P450
metabolic isoenzymes 3A and 2B6. Co-administration of VIRAMUNE and
drugs primarily metabolized by CYP3A or CYP2B6 may result in decreased
plasma concentrations of these drugs and attenuate their therapeutic
effects.
While primarily an inducer
of cytochrome P450 3A and 2B6 enzymes, nevirapine may also inhibit
this system. Among human hepatic cytochrome P450s, nevirapine was
capable in vitro of inhibiting the 10-hydroxylation
of (R)-warfarin (CYP3A). The estimated Ki for
the inhibition of CYP3A was 270 micromolar, a concentration that is
unlikely to be achieved in patients as the therapeutic range is less
than 25 micromolar. Therefore, nevirapine may have minimal inhibitory
effect on other substrates of CYP3A.
Nevirapine does not appear to affect the plasma concentrations
of drugs that are substrates of other CYP450 enzyme systems, such
as 1A2, 2D6, 2A6, 2E1, 2C9, or 2C19.
Table 5 (see below) contains the results of drug interaction
trials performed with VIRAMUNE and other drugs likely to be co-administered.
The effects of VIRAMUNE on the AUC, Cmax, and
Cmin of co-administered drugs are summarized.
Table 5 Drug Interactions: Changes in Pharmacokinetic Parameters
for Co-administered Drug in the Presence of VIRAMUNE (All interaction
trials were conducted in HIV-1 positive subjects)
§ = Cmin below detectable level
of the assay ↑ = Increase, ↓ = Decrease, ⇔ = No Effect
a For information regarding clinical
recommendations, see Drug Interactions (7)
.
b Pediatric
subjects ranging in age from 6 months to 12 years
c Parallel group design; n for VIRAMUNE+lopinavir/ritonavir,
n for lopinavir/ritonavir alone.
d Parallel group design; n=23 for atazanavir/ritonavir + nevirapine,
n=22 for atazanavir/ritonavir without nevirapine. Changes in atazanavir
PK are relative to atazanavir/ritonavir 300/100 mg alone.
e Based on between-trial comparison.
f Based on historical controls. |
Co-administered
Drug
|
Dose of Co-administered
Drug
|
Dose Regimen of
VIRAMUNE
|
n
|
% Change of Co-administered Drug Pharmacokinetic Parameters (90%
CI)
|
Antiretrovirals
|
AUC
|
Cmax
|
Cmin
|
Atazanavir/Ritonavira, d
|
300/100 mg QD day
4–13, then 400/100 mg QD, day 14–23 |
200 mg BID day 1-23. Subjects
were treated with nevirapine prior to trial entry. |
23 |
Atazanavir 300/100
mg
↓42 (↓52 to ↓29)
|
Atazanavir 300/100
mg
↓28 (↓40 to ↓14)
|
Atazanavir 300/100
mg
↓72 (↓80 to ↓60)
|
Atazanavir 400/100
mg
↓19 (↓35 to ↑2)
|
Atazanavir 400/100
mg
↑2 (↓15 to ↑24)
|
Atazanavir 400/100
mg
↓59 (↓73 to ↓40)
|
Darunavir/Ritonavir e
|
400/100 mg BID |
200 mg BID |
8 |
↑24 (↓3 to ↑57)
|
↑40 (↑14 to ↑73)
|
↑2 (↓21 to ↑32)
|
Didanosine |
100-150 mg BID |
200 mg QD x 14 days; 200 mg BID x 14 days |
18 |
⇔ |
⇔ |
§ |
Efavirenza
|
600 mg QD |
200 mg QD x 14 days; 400 mg QD x 14 days |
17 |
↓28 (↓34 to ↓14) |
↓12 (↓23 to ↑1) |
↓32 (↓35 to ↓19) |
Fosamprenavir |
1400 mg BID |
200 mg BID. Subjects were treated with
nevirapine prior to trial entry. |
17 |
↓33 (↓45 to ↓20)
|
↓25 (↓37 to ↓10)
|
↓35 (↓50 to ↓15)
|
Fosamprenavir/Ritonavir |
700/100 mg BID |
200 mg BID. Subjects were treated with
nevirapine prior to trial entry |
17 |
↓11 (↓23 to ↑3)
|
⇔
|
↓19 (↓32 to ↓4)
|
Indinavira
|
800 mg q8H |
200 mg QD x 14 days; 200 mg BID x 14 days |
19 |
↓31 (↓39 to ↓22) |
↓15 (↓24 to ↓4) |
↓44 (↓53 to ↓33) |
Lopinavira, b
|
300/75 mg/m2 (lopinavir/ ritonavir) b
|
7 mg/kg or 4 mg/kg QD x 2 weeks; BID x 1
week |
12, 15 c
|
↓22 (↓44 to ↑9) |
↓14 (↓36 to ↑16) |
↓55 (↓75 to ↓19) |
Lopinavira
|
400/100 mg BID (lopinavir/ritonavir) |
200 mg QD x 14 days; 200 mg BID >1 year |
22, 19 c
|
↓27 (↓47 to ↓2) |
↓19 (↓38 to ↑5) |
↓51 (↓72 to ↓26) |
Maraviroc f
|
300 mg SD |
200 mg BID |
8 |
↑1 (↓35 to ↑55) |
↑54 (↓6 to ↑151) |
⇔ |
Nelfinavira
|
750 mg TID |
200 mg QD x 14 days; 200 mg BID x 14 days |
23 |
⇔ |
⇔ |
↓32 (↓50 to ↑5) |
Nelfinavir-M8 metabolite |
|
|
|
↓62 (↓70 to ↓53) |
↓59 (↓68 to ↓48) |
↓66 (↓74 to ↓55) |
Ritonavir |
600 mg BID |
200 mg QD x 14 days; 200 mg BID x 14 days |
18 |
⇔ |
⇔ |
⇔ |
Stavudine |
30-40 mg BID |
200 mg QD x 14 days; 200 mg BID x 14 days |
22 |
⇔ |
⇔ |
§ |
Zalcitabine |
0.125-0.25 mg TID |
200 mg QD x 14 days; 200 mg BID x 14 days |
6 |
⇔ |
⇔ |
§ |
Zidovudine |
100-200 mg TID |
200 mg QD x 14 days; 200 mg BID x 14 days |
11 |
↓28 (↓40 to ↓4) |
↓30 (↓51 to ↑14) |
§ |
Other Medications
|
AUC
|
Cmax
|
Cmin
|
Clarithromycina
|
500 mg BID |
200 mg QD x 14 days; 200 mg BID x 14 days |
15 |
↓31 (↓38 to ↓24) |
↓23 (↓31 to ↓14) |
↓56 (↓70 to ↓36) |
Metabolite 14-OH-clarithromycin |
|
|
|
↑42 (↑16 to ↑73) |
↑47 (↑21 to ↑80) |
⇔ |
Ethinyl estradiola
and
Norethindronea
|
0.035 mg (as Ortho-Novum® 1/35) |
200 mg QD x 14 days; 200 mg
BID x 14 days |
10 |
↓20 (↓33 to ↓3) |
⇔ |
§ |
1 mg (as Ortho-Novum® 1/35) |
↓19 (↓30 to ↓7) |
↓16 (↓27 to ↓3) |
§ |
Depomedroxy-progesterone acetate |
150 mg every 3 months |
200 mg QD x 14 days; 200 mg BID x 14 days |
32 |
⇔ |
⇔ |
⇔ |
Fluconazole |
200 mg QD |
200 mg QD x 14 days; 200 mg BID x 14 days |
19 |
⇔ |
⇔ |
⇔ |
Ketoconazolea
|
400 mg QD |
200 mg QD x 14 days; 200 mg BID x 14 days |
21 |
↓72 (↓80 to ↓60) |
↓44 (↓58 to ↓27) |
§ |
Methadonea
|
Individual Subject Dosing |
200 mg QD x 14 days; 200 mg BID ≥7 days |
9 |
In a controlled pharmacokinetic
trial with 9 subjects receiving chronic methadone to whom steady-state
nevirapine therapy was added, the clearance of methadone was increased
by 3-fold, resulting in symptoms of withdrawal, requiring dose adjustments
in 10 mg segments, in 7 of the 9 subjects. Methadone did not have
any effect on nevirapine clearance. |
Rifabutina
|
150 or 300 mg QD |
200 mg QD x 14 days; 200 mg BID x 14 days |
19 |
↑17 (↓2 to ↑40) |
↑28 (↑9 to ↑51) |
⇔ |
Metabolite 25-O-desacetyl-rifabutin |
|
|
|
↑24 (↓16 to ↑84) |
↑29 (↓2 to ↑68) |
↑22 (↓14 to ↑74) |
Rifampina
|
600 mg QD |
200 mg QD x 14 days; 200 mg BID x
14 days |
14 |
↑11 (↓4 to ↑28) |
⇔ |
§ |
Because of the design of the drug
interaction trials (addition of 28 days of VIRAMUNE therapy to existing
HIV-1 therapy), the effect of the concomitant drug on plasma nevirapine
steady-state concentrations was estimated by comparison to historical
controls.
Administration of rifampin
had a clinically significant effect on nevirapine pharmacokinetics,
decreasing AUC and Cmax by greater than 50%.
Administration of fluconazole resulted in an approximate 100% increase
in nevirapine exposure, based on a comparison to historic data [see Drug Interactions (7) ]. The effect of other drugs listed in Table 5 on nevirapine pharmacokinetics
was not significant. No significant interaction was observed when
tipranavir was co-administered with low-dose ritonavir and nevirapine.
Microbiology
Mechanismof 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.
AntiviralActivity
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
14-302 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 VIRAMUNE XR and
immediate-release VIRAMUNE 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 VIRAMUNE
XR treatment group and 88% (30/34) of the subjects in the immediate-release
VIRAMUNE 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 VIRAMUNE XR treatment and 25 subjects failing immediate-release
VIRAMUNE treatment. On-therapy isolates from 1 subject in VIRAMUNE
XR treatment group developed a novel amino acid substitution Y181I
and isolates from another subject in the immediate-release VIRAMUNE
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.
NONCLINICAL TOXICOLOGY
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 VIRAMUNE.
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.
|
CLINICAL STUDIES
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 VIRAMUNE + lamivudine
+ background therapy versus lamivudine + background therapy in NNRTI-naïve
subjects. Treatment doses were VIRAMUNE, 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
per mL (38,291 copies per 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 per mL and not previously
failed at 48 weeks. Treatment response and outcomes are shown in Table
6.
Table 6 BI 1090 Outcomes Through 48 Weeks
1 including change to open-label
nevirapine
2 includes withdrawal
of consent, lost to follow-up, non-compliance with protocol, other
administrative reasons |
Outcome
|
VIRAMUNE (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 |
|
The change from baseline in CD4+ cell count through one year of therapy was significantly
greater for the VIRAMUNE group compared to the placebo group for the
overall trial population (64 cells/mm3 versus
22 cells/mm3, respectively), as well as
for subjects who entered the trial as treatment-naïve or having received
only ZDV (85 cells/mm3 versus 25 cells/mm3, respectively).
At two years into the trial, 16% of subjects on VIRAMUNE 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 200-600
cells/mm3 at baseline. BI 1046 compared
treatment with VIRAMUNE+zidovudine+didanosine to VIRAMUNE+zidovudine
and zidovudine+didanosine. Treatment doses were VIRAMUNE 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
per 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
per mL and not previously failed at 48 weeks. The virologic responder
rates at 48 weeks were 45% for subjects treated with VIRAMUNE+zidovudine+didanosine,
19% for subjects treated with zidovudine+didanosine, and 0% for subjects
treated with VIRAMUNE+zidovudine.
CD4+ cell counts in the VIRAMUNE+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 VIRAMUNE+ZDV group mean decreased by 6 cells/mm3 below baseline.
Pediatric Patients
The pediatric safety and efficacy of VIRAMUNE was examined in BI
Trial 1100.1368, an open-label, randomized clinical trial performed
in South Africa in which 123 HIV-1 infected treatment-naïve subjects
between 3 months and 16 years of age received VIRAMUNE oral suspension
for 48 weeks. Subjects were divided into 4 age groups (3 months to
less than 2 years, 2 to less than 7 years, 7 to less than 12 years,
and 12 to less than or equal to 16 years) and randomized to receive
one of two VIRAMUNE doses, determined by 2 different dosing methods
[body surface area (150 mg/m2) and weight-based
dosing (4 or 7 mg per kg)] in combination with zidovudine and lamivudine [see Adverse Reactions , Use
in Specific Populations , and
Clinical Pharmacology ]. The total daily dose of VIRAMUNE did not exceed 400 mg in either
regimen. There were 66 subjects in the body surface area (BSA) dosing
group and 57 subjects in the weight-based (BW) dosing group.
Baseline demographics included: 49% male;
81% Black and 19% Caucasian; 4% had previous exposure to ARVs. Subjects
had a median baseline HIV-1 RNA of 5.45 log10 copies per mL and a median baseline CD4+ cell count of 527 cells/mm3 (range 37-2279).
One hundred and five (85%) completed the 48-week period while 18 (15%)
discontinued prematurely. Of the subjects who discontinued prematurely,
9 (7%) discontinued due to adverse reactions and 3 (2%) discontinued
due to virologic failure. Overall the proportion of subjects who achieved
and maintained an HIV-1 RNA less than 400 copies per mL at 48 weeks
was 47% (58/123).
|