リトナビル 化学特性,用途語,生産方法
外観
白色～ほとんど白色、結晶性粉末～粉末
溶解性
メタノール及びエタノールに溶けやすく、水にほとんど溶けない。
用途
HIV プロテアーゼ阻害剤です。
タンパク質前駆体の開裂に関与する HIV プロ
テアーゼを阻害することにより、成熟ウイル
スの産生を阻害します。
効能
抗ウイルス薬, HIVプロテアーゼ阻害薬
商品名
ノービア (アッヴィ)
使用上の注意
アルゴン封入
説明
Ritonavir (brand name: Norvir) was launched in Germany, the UK and US for treatment of advanced HIV in combination with antiretroviral nucleoside analogs in a record 72 days by the FDA. It is an inhibitor of HIV aspartic protease which is critical in the processing of a propeptide into the gag, gag-pol gene products and the protease itself. This inhibition results in the release of non-infectous immature virus particles. It is greater than 500-fold more selective for viral aspartic protease than the human version, has good oral bioavailability and may increase the bioavailability of other protease inhibitors. Ritonavir was able to increase the CD4 and CD8 lymphocyte count as well as reduce viral RNA. It is more potent than saqunavir and comparible in potency to zidovudine and lamivudine.
化学的特性
Ritonavir is a white-to-light-tan powder with a bitter metallic taste. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water. It is an inhibitor of HIV protease with activity against the Human Immunodeficiency Virus (HIV).
使用
Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1-infected patients. Ritonivir is an HIV protease inhibitor (EC50 = 25 nM) that also inhibits CYP3A4, the primary cytochrome P450 isoform that metabolizes protease inhibitors. Through CYP3A4 inhibition, low doses of ritonivir can reduce the metabolism of concomitantly administered protease inhibitiors, enhancing their bioavailability and efficacy.
定義
ChEBI: Ritonavir is an L-valine derivative that is L-valinamide in which alpha-amino group has been acylated by a [(2-isopropyl-1,3-thiazol-4-yl)methyl]methylcarbamoyl group and in which a hydrogen of the carboxamide amino group has been replaced by a (2R,4S,5S)-4-hydroxy-1,6-diphenyl-5-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}hexan-2-yl group. A CYP3A inhibitor and antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS, it is often used as a fixed-dose combination with another protease inhibitor, lopinavir. Also used in combination with dasabuvir sodium hydrate, ombitasvir and paritaprevir (under the trade name Viekira Pak) for treatment of chronic hepatitis C virus genotype 1 infection as well as cirrhosis of the liver. It has a role as an antiviral drug, a HIV protease inhibitor, an environmental contaminant and a xenobiotic. It is a member of 1,3-thiazoles, a L-valine derivative, a carbamate ester, a member of ureas and a carboxamide.
適応症
Ritonavir is a prescription medicine approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV infection in adults and children older than 1 month. Although Ritonavir is a potent inhibitor of HIV-1 and HIV-2 protease, it is not well tolerated in higher doses. It is mainly used in low doses to increase blood levels of other protease inhibitors and to extend their dosing interval. Ritonavir is more commonly associated with gastrointestinal side effects, altered taste sensation, paresthesias, and hypertriglyceridemia than are other protease inhibitors. Pancreatitis may occur in the presence or absence of hypertriglyceridemia.
抗菌性
Ritonavir is active against HIV-1 and, to a lesser extent, HIV-2.
獲得抵抗性
At antiretroviral doses resistance is associated with the presence
of specific amino acid substitutions in the HIV protease
at positions 82 and 84. Concern about the risk for
selection of ritonavir resistance when used at a subtherapeutic
‘booster’ dose has so far not been borne out by clinical
experience.
一般的な説明
Ritonavir belongs to the group of protease inhibitors, which block the part of HIV called protease. Its mode of action involves binding to the protease active site and inhibiting the activity of the enzyme.
生物活性
Ritonavir is an HIV protease inhibitor. It inhibits recombinant HIV-1 protease by 79% when used at a concentration of 0.5 nM. It inhibits HIV-1
3B-induced cell death in MT-4 human T cell leukemia cells (EC
50 = 25 nM) as well as cell death induced by HIV-1
LAI, HIV-2
ROD, and HIV-2
EHO in human MT-2 cells (IC
50s = 0.045, 0.13, and 0.24 μM, respectively). Ritonavir also inhibits the cytochrome P450 (CYP) isoform CYP3A (IC
50 = 0.14 μM). It inhibits CYP-mediated oxidative metabolism of the HIV protease inhibitors saquinavir , indinavir , nelfinavir , and amprenavir in rat and human liver microsomes in a concentration-dependent manner. Ritonavir (10 mg/kg) also prevents decreases in plasma levels of these four compounds in rats. Formulations containing ritonavir have been used in the treatment of HIV-1 infection.
作用機序
Because of the strong CYP450-inhibiting effects of ritonavir, the drug has found value when used in
fixed-dosage combinations with other PIs to block their metabolism and act as a booster for these drugs
(lopinavir/ritonavir and tipranavir/ritonavir). In these cases, ritonavir is used in a subtherapeutic dose but
boosts the effectiveness of the coadministered drug. The utilization of ritonavir in a therapeutic dose for
treating HIV infections appears to be decreasing, but its utilization as a booster drug is finding favor.
薬物動態学
Oral absorption: Not known/available
C
max 600 mg twice daily: c. 11.2 mg/L
C
min 600 mg twice daily: c. 3.7 mg/L
Plasma half-life: c. 3–5 h
Volume of distribution: c. 0.3–0.6 L/kg
Plasma protein binding: c. 97%
Absorption and distribution
Fasting and high-fat meals had no appreciable effect on oral absorption. It penetrates poorly into the CNS. The semen:plasma ratio is <0.04. It is distributed into breast milk.
Metabolism and excretion
Four oxidized metabolites have been identified, the major of which retains antiretroviral activity. Around 11% of the dose is excreted in urine, 4% as unchanged drug. The remainder is found in feces. Metabolites are eliminated primarily via the feces.
No dose adjustment is recommended in mild to moderate hepatic impairment. It should not be given to patients with severe hepatic impairment, nor should it be given as a pharmacokinetic enhancer to patients with decompensated liver disease.
副作用
Full (antiretroviral) doses are associated with nausea, vomiting,
diarrhea and fatigue in >20% of subjects. The degree to which
ritonavir at low dose is associated with specific adverse events
is uncertain. In HIV-negative healthy volunteers given ‘booster’
doses of 100 mg every 12 h, the concentration of total cholesterol,
low-density cholesterol and triglycerides all increased, and
the concentration of high-density cholesterol concentration fell.
薬物相互作用
Ritonavir-boosted nirmatrelvir has significant drug-drug interactions, primarily due to the ritonavir component of the combination. Boosting with ritonavir, which is a strong CYP3A inhibitor and a P-glycoprotein inhibitor, is required to increase the exposure of nirmatrelvir to a concentration that is effective against SARS-CoV-2. However, it may also increase concentrations of certain concomitant medications, thereby increasing the potential for serious and sometimes life-threatening drug toxicities. Additionally, ritonavir is an inhibitor, inducer, and substrate of various other drug-metabolizing enzymes and/or drug transporters.
リトナビル 上流と下流の製品情報
原材料
準備製品