チプラナビル 化学特性,用途語,生産方法
外観
白色～うすい褐色、結晶～粉末
溶解性
アセトニトリル-メタノールに可溶
効能
抗ウイルス薬, HIVプロテアーゼ阻害薬
化学的特性
White Solid
定義
ChEBI: A pyridine-2-sulfonamide substituted at C-5 by a trifluoromethyl group and at the sulfonamide nitrogen by a dihydropyrone-containing m-tolyl substituent. It is an HIV-1 protease inhibitor.
獲得抵抗性
In a study of 105 viruses resistant to other protease inhibitors,
90% exhibited a more than four-fold decrease in susceptibility and
2% high-level resistance (>10-fold decrease). The predominant
emerging mutations in use with ritonavir are L33F/I/V, V82T/L
and I84V. Combination of all three of these mutations is usually
required for reduced susceptibility. Mutations at positions 47, 58
and 74 are also associated with resistance.
一般的な説明
Tipranavir is unique among the PIs because it is not a peptidomimeticcompound. It does appear to bind to the activesite of HIV-1 protease the same as the peptidomimetics do.The benefit of this agent is that, because it is a differentchemical structure, cross-resistance does not develop tothe same extent as seen with the peptidomimetics. Thedrug is administered with a booster dose of ritonavir. Thisprotocol inhibits CYP3A4, causing the levels of tipranavirto increase.
応用例（製薬）
A non-peptidic protease inhibitor formulated as capsules or
solution for oral use.
作用機序
Tipranavir appears to be bound to the same active site of HIV-1 protease as the peptidomimetics are, but because of its different chemical structure, cross-resistance is significantly less than that seen between the peptidomimetics. The drug suppresses viral replication in various strains of HIV-1 in vitro, and when combined with azothymidine or delaviridine, synergistic activity is noted in vitro. Tipranavir has an advantage over the other PIs in that it is not as strongly bound to plasma protein as the earlier PIs are, a property that reduces the 90% inhibition concentration.
薬物動態学
Oral absorption: Not known/available
C
max 500 mg + 200 mg ritonavir twice: c. 57.2 mg/L (female);
daily: 46.8 mg/L (male)
C
min 500 mg + 200 mg ritonavir twice: c. 25.1 mg/L (female);
daily: 21.5 mg/L (male)
Plasma half-life: c. 5.5 h (female); 6 h (male)
Volume of distribution: Not known/available
Plasma protein binding: >99.9%
Absorption and distribution
The combination with ritonavir may be taken with or without food. No studies have been conducted to determine the distribution into human CSF, semen or breast milk.
Metabolism and excretion
Metabolism in the presence of 200 mg ritonavir is minimal. Around 82% is excreted in the feces and 4% in the urine. In mild hepatic impairment it should be used with caution; it should not be used in moderate or severe hepatic impairment.
臨床応用
Treatment (in combination with other antiretroviral drugs) of HIV-1 infection
in patients unresponsive to more than one other protease inhibitor
副作用
Adverse effects include nausea, vomiting, diarrhea, fatigue
and headache. In studies of ritonavir-boosted regimens higher
rates of hepatotoxicity have been observed with tipranavir
than with other protease inhibitors. In addition, 14 reports of
intracranial bleeding (eight fatal cases) associated with tipranavir
have been reported. It has been associated with dyslipidemia
to a greater extent than other protease inhibitors.
チプラナビル 上流と下流の製品情報
原材料
準備製品