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効能
抗ウイルス薬, 逆転写酵素阻害薬
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商品名
インテレンス (ヤンセンファーマ)
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説明
Etravirine is a second-generation NNRTI. It is indicated for use in
combination with other antiretroviral agents for treating HIV-1 infection in
treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to the currently available NNRTIs and
other antiretroviral agents. The NNRTIs, along with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs), are important
components of the combination regimens currently used to treat HIV-1
infection. The NRTIs/NtRTIs act by competing with the natural nucleotide
substrates of reverse transcriptase for incorporation into viral DNA
and subsequent chain termination. By contrast, the NNRTIs bind to an
allosteric site of the enzyme and disrupt the DNA polymerase function by
inducing conformational changes to the catalytic site. The allosteric
binding nature of NNRTIs generally results in improved safety profile
since there is no known human homolog for the drug-binding site of
the enzyme.
As with other NNRTIs, etravirine has
many drug–drug interactions. It is a substrate of CYP3A4, CYP2C9,
and CYP2C19, an inducer of 3A4, and an inhibitor of 2C9 and 2C19.
Caution should be used with co-administration of inducers, inhibitors, or
substrates of these enzymes. Etravirine can be synthesized starting from
5-bromo-2,4,6-trichloropyrimidine through three successive nucleophilic
substitution reactions. Initial displacement with 4-aminobenzonitrile using
Hu¨nig’s base, followed by reaction with sodium salt of 4-hydroxy-3,5-
dimethylbenzonitrile, and subsequent ammonolysis reaction with ammonia in dioxane under pressure affords etravirine.
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化学的特性
White to Off-White Solid
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使用
Etravirine is an antiretroviral (anti-HIV) drug that is part of the non nucleoside reverse transcriptase inhibitor (NNRTIs or Non Nukes) family. It is used together with other antiretrovirals in treatment-experienced adult patients, who have failed previous therapy, and have HIV-1 strains which are resistant to other retrovirals and NNRTIs. Etravirine is used to delay the progression of HIV infection. By using etravirine, your immune system should improve (increase in CD4 + count) and you will be better protected against opportunistic infections.
Etravirine does not cure AIDS or completely kill the HIV virus, but helps to prevent further damage by slowing down the production of new viruses. Treatment with etravirine does not reduce the risk of passing infection on to others. You will still be able to pass HIV by sexual contact, by blood transfer or by sharing needles. You should always use appropriate precautions to prevent passing HIV on to others.
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定義
ChEBI: An aminopyrimidine that consists of 2,6-diaminopyrimidine bearing a bromo substituent at position 5, a 4-cyano-2,6-dimethylphenoxy substituent at position 4 and having a 4-cyanophenyl substituent attached to the 2-amino group. NNRTI of HIV-1, binds directl
to RT and blocks RNA-dependent and DNA-dependent DNA polymerase activities
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獲得抵抗性
Various mutations are associated with a decreased virological
response. Single codon substitutions at positions 100, 101
and 181 are considered major mutations. A single K103N
mutation is not associated with resistance.
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応用例（製薬）
A comprehensive analysis of baseline resistance data from
the DUET-1 and DUET-2 studies has identified a list of
17 etravirine resistance associated mutations: V901, A98G,
L100L, K101E/H/I, V1061, E138A, V179D/F/T, Y181C/L/V,
G190A/S, and M230L. A single K103N mutation is not associated
with resistance to etravirine.
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作用機序
Etravirine binds directly to reverse transcriptase and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. Etravirine does not inhibit the human DNA polymerases alpha, beta, and gamma.
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薬物動態学
Oral absorption: Not known/available
Cmax 200 mg oral twice daily: c. 959 ng/mL
Cmin 200 mg oral twice daily: c. 469 ng/mL
Plasma half-life: c. 36 h
Volume of distribution: Not known/available
Plasma protein binding: >99%
Administration with food improves the bioavailability and
reduces interpatient variability. It undergoes oxidative metabolism
by cytochrome P450 systems. Around 93.7% and 1.2%
of an administered dose can be retrieved in the feces and
urine, respectively, mostly as unchanged drug.
Details of distribution into CSF, semen and breast milk
and recommendations for dose adjustment in patients with
hepatic impairment are not yet available.
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臨床応用
Treatment of HIV-1 infection in adults (in combination with other
antiretroviral drugs)
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副作用
In the phase III studies around 15% of patients experienced
erythematous or maculopapular rashes of mild or moderate
severity; most resolved with continued dosing, but treatment
was discontinued in 2% of patients. Rare cases of Stevens–
Johnson syndrome have been reported.
Other common adverse events are diarrhea, nausea, headache
and fatigue. Dyslipidemia and raised pancreatic amylase
occur in some patients.
