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効能
抗ウイルス薬, HIVプロテアーゼ阻害薬
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説明
Lopinavir, the sixth HIV protease inhibitor in the “navir” class, was launched in coformulation
with ritonavir, another HIV protease inhibitor already marketed (Abbott, 1996);
this original formulation was introduced as Kaletra for use in combination with either
nucleoside or non-nucleoside reverse transcriptase inhibitors for the treatment of AIDS in
adults and children. Lopinavir is a peptidomimetic compound with a structural core
identical to that of ritonavir, on which terminal groups, particularly a modified valine, were
introduced by peptide coupling procedures. Lopinavir is a potent competitive inhibitor of
HIV-I protease exhibiting high potential against ritonavir-resistant mutations. In several
animal species, pharmacokinetic studies with the lopinavirlritonavir association showed
that the modest properties of lopinavir were significantly improved in presence of ritonavir,
in terms of Cmax and duration of action. Ritonavir inhibits the P450 isoenzyme CYP3A4
and the human liver microsomal metabolism of lopinavir, so strongly amplifying plasma
levels of this latter component. In AIDS patients, the plasma HIV RNA level was
considerably reduced and the CD4+ T-cell counts increased after administration of
lopinavir combined with relatively small doses of ritonavir. Kaletra is intended to be used
jointly with other antiretroviral agents.
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化学的特性
Lopinavir is a white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.
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使用
Lopinavir is a potent HIV protease inhibitor with Ki of 1.3 pM
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定義
ChEBI: Lopinavir is a dicarboxylic acid diamide that is amphetamine is substituted on nitrogen by a (2,6-dimethylphenoxy)acetyl group and on the carbon alpha- to nitrogen by a (1S,3S)-1-hydroxy-3-{[(2S)-3-methyl-2-(2-oxotetrahydropyrimidin-1-yl)butanoyl]amino}-4-phenylbutyl group. An antiretroviral of the protease inhibitor class, it is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir. It has a role as an antiviral drug, a HIV protease inhibitor and an anticoronaviral agent. It is a member of amphetamines and a dicarboxylic acid diamide.
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適応症
Lopinavir is available in the United States only as a
fixed-dose combination with ritonavir (Kaletra). In this
regimen, a low dose of ritonavir is used to inhibit the
rapid inactivation of lopinavir by CYP3A4.
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抗菌性
Lopinavir is active against HIV-1 and HIV-2.
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獲得抵抗性
Significant resistance to the antiretroviral efficacy of ritonavirbooted
lopinavir occurs as a result of amino acid substitutions
at positions 32, 47 and 82 in the protease region. Protease
inhibitor resistance is uncommon in patients identified with
early failure of combination therapy with ritonavir boostedlopinavir
and nucleotide reverse transcriptase inhibitors.
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一般的な説明
Lopinavir is a protease inhibitor that has been approved foruse in combination with ritonavir for patients with HIV whohave not responded to other treatment modalities. Lopinaviris used in excess over ritonavir. Ritonavir at amounts givenhas no antiretroviral activity, Ritonavir inhibits lopinavir’smetabolism by CYP3A4, causing a higher level of lopinavirin the system. The combination is the first protease inhibitorapproved for patients as young as 6 months of age.
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薬物動態学
Oral absorption: Not known/available
Cmax 400 mg + ritonavir 100 mg twice daily: c. 9.6 mg/L
Cmin 400 mg + ritonavir 100 mg twice daily: c. 5.5 mg/L
Plasma half-life: c. 5–6 h
Volume of distribution: Not known/available
Plasma protein binding: c. 98–99%
Absorption and distribution
The absorption of lopinavir–ritonavir in capsule or liquid form is favorably affected by the presence of food, particularly if high in fat. The CNS penetration is good. It has a semen:plasma ratio of 0.07. It is distributed into breast milk.
Metabolism
Lopinavir is extensively metabolized by the CYP3A4 system, but this is inhibited by ritonavir.
Excretion
Over an 8-day period after single dosing with the combined formulation, around 10% and 83% of the administered dose is recovered in urine and feces, respectively. Less than 3% of the dose is recovered as unchanged drug in urine and 20% in feces. In mild to moderate hepatic impairment, an increase in exposure of approximately 30% is observed, but is probably not clinically relevant. It should be avoided in severe hepatic impairment.
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臨床応用
Treatment of HIV infection (in combination with ritonavir and other
antiretroviral agents)
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副作用
The most common adverse events seen in trials of complex antiretroviral
regimens were diarrhea, nausea, headache, fatigue,
vomiting and rash. Ritonavir-boosted lopinavir is associated
with a dyslipidemia profile characteristic of those treated with
other protease inhibitors boosted with 200 mg of ritonavir.
