In large randomized controlled trials, serum aminotransferase elevations more than 5 times the upper limit of normal (ULN) occurred in 1% to 2% of Viekira Pak treated patients. Interestingly, this rate was lower than occurred with placebo therapy (3% to 7%). The elevations were generally asymptomatic and short lived, resolving with or without dose modification and requiring drug discontinuation in approximately 1% of patients. Despite the frequency of serum enzyme elevations during therapy, clinically apparent liver injury was rarely reported in preregistration studies. However, since the general availability of Viekira Pak in the United States and during years of clinical use elsewhere, occasional instances of marked serum aminotransferase elevations with symptoms and mild jaundice have been reported, although not described in the published literature. Furthermore, some patients with chronic hepatitis C and advanced cirrhosis have developed sudden hepatic decompensation during therapy with D-O-P/r. Similar episodes have been described in patients receiving other oral antiviral combinations such as sofosbuvir with daclatasvir, ledipasvir or simeprevir. Thus, this phenomenon may be unrelated to a specific agent, but rather common to all potent antiviral therapies for hepatitis C and perhaps is a paradoxical response to sudden clearance of HCV. Alternatively, these episodes may be spontaneous, coincidental and unrelated to the antiviral therapy. Trials of these therapies in patients with cirrhosis have not been placebo controlled so that the rate of spontaneous hepatic decompensation in patients with cirrhosis due to hepatitis C is not well defined. Whatever the reason, the occurrence of decompensation in up to 10% of patients with cirrhosis undergoing potent antiviral therapy makes prospective monitoring advisable and prompt discontinuation of treatment if evidence of hepatic failure supervenes.
Thus, the five antiviral compounds included in Viekira Pak regimens (dasabuvir, ombitasvir, paritaprevir, ritonavir and ribavirin) have been linked to instances of sudden ALT elevations during therapy, but uncommonly to clinically apparent liver injury. In patients with preexisting cirrhosis, antiviral therapy with Viekira Pak has been linked to episodes of lactic acidosis and hepatic decompensation. The cause of these sudden, severe adverse events is unknown but they are usually severe and life threatening, requiring prompt discontinuation of treatment, intensive care management and consideration of emergency liver transplantation.
Likelihood score: C (probable cause of liver injury arising in patients with pre-existing cirrhosis).
The most common adverse effects of Viekira Pak either in combination with or without [DB00811] were pruritus, nausea, insomnia, and asthenia [FDA Label]. The most common adverse effects of Technivie with or without [DB00811] were asthenia, fatigue, nausea, insomnia and pruritus [L866].
来源:DrugBank
毒理性
蛋白质结合
奥比他韦99.9%与人血浆蛋白结合（美国食品药品监督管理局标签）。
Ombitasvir is 99.9% bound to human plasma proteins [FDA Label].
Ombitasvir reaches peak plasma concentration 5 hours after administration [FDA Label]. It has an absolute bioavailability of 48%. Taking ombitasvir with high or normal fat meals increases exposure by 1.76 or 1.82 fold respectively.
Ombitasvir is mainly excreted in the feces (90.2%) with very little excreted in the urine (1.91%) [FDA Label]. 87.8% and 0.03% of the dose excreted in the feces and urine respectively is present as the parent compound.
来源:DrugBank
吸收、分配和排泄
分布容积
奥比他韦在稳态下的分布体积为173升[美国食品药品监督管理局标签]。
Ombitasvir has a volume of distribution at steady state of 173 liters [FDA Label].
Compounds effective in inhibiting replication of Hepatitis C virus (“HCV”) are described. This invention also relates to processes of making such compounds, compositions comprising such compounds, and methods of using such compounds to treat HCV infection.
[EN] COMBINATIONS OF HEPATITIS C VIRUS INHIBITORS<br/>[FR] ASSOCIATIONS D'INHIBITEURS DU VIRUS DE L'HÉPATITE C
申请人：BRISTOL MYERS SQUIBB CO
公开号：WO2015005901A1
公开（公告）日：2015-01-15
The present disclosure is generally directed to antiviral compounds, and more specifically directed to combinations of compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such combinations, and methods for inhibiting the function of the NS5A protein.
The present disclosure relates generally to toll like receptor modulator compounds, such as diamino pyrido[3,2 D]pyrimidine compounds and pharmaceutical compositions which, among other things, modulate toll-like receptors (e.g. TLR-8), and methods of making and using them.
The disclosure is related to anti-viral compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.
[EN] 4,6-DIAMINO-PYRIDO[3,2-D]PYRIMIDINE DERIVATIES AS TOLL LIKE RECEPTOR MODULATORS<br/>[FR] DÉRIVÉS DE 4,6-DIAMINO-PYRIDO [3,2-D] PYRIMIDINE EN TANT QUE MODULATEURS DU RÉCEPTEUR DE TYPE TOLL
申请人：GILEAD SCIENCES INC
公开号：WO2018045150A1
公开（公告）日：2018-03-08
This application relates generally to toll like receptor modulator compounds as defined below and pharmaceutical compositions which, among other things, modulate toll-like receptors (e.g. TLR8), and methods of making and using them.
