Following a single oral administration of 200 mg (1.3 times the recommended dosage) (14)C-simeprevir to healthy subjects, the majority of the radioactivity in plasma (mean: 83%) was accounted for by unchanged drug and a small part of the radioactivity in plasma was related to metabolites (none being major metabolites). Metabolites identified in feces were formed via oxidation at the macrocyclic moiety or aromatic moiety or both and by O-demethylation followed by oxidation.
Simeprevir is metabolized in the liver. In vitro experiments with human liver microsomes indicated that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A system. Involvement of CYP2C8 and CYP2C19 cannot be excluded. Co-administration of Olysio with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir, and co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir.
The in vitro metabolism of 14C-TMC435 was investigated in hepatocytes and liver microsomes of mouse, rat, rabbit, monkey and human. The metabolic activity reported in vitro from animals and man was low. Phase II conjugation pathways of Phase I metabolites were formed in hepatocytes. Parent TMC435 was found in much greater levels than any metabolite in vitro. More than 20 metabolites were identified. The metabolic Phase I route of highest importance were O-demethylation of unchanged drug (particularly in animals), oxidation of unchanged drug and oxidized metabolites (particularly in monkey and man) and glucuronidation was the major Phase II of oxidized metabolites (less in human). Only one human metabolite identified in vitro not seen in rat or dog was M22 (oxidized unchanged drug) but this metabolite was identified in rat (feces). In vivo data reveals that the main moiety present in plasma of rat, dog and man was parent TMC435. The major metabolites reported in vivo in plasma from animals and human were M18 and M21. O-desmethyl-TMC435 M21 was the only common circulating metabolite found in rat dog and human plasma (M21: 8% of the mean TMC435 plasma and only small traces in dogs), while M18 was common to plasma of rats and dogs but with respect to the parent compound they appeared with low concentrations (M18: between 28.9% and 12.5% in rats, with only small traces in dogs). Only traces of metabolites M18, M21 and M8 formed by O-demethylation and oxidation at the aromatic moiety were reported in dog plasma. M21 represents less than 10% of unchanged drug and also total radioactivity therefore systemic exposure to M21 was not assessed in the safety evaluation studies. M21 did not appear to accumulate in man. In bile from rats, moderately high levels of parent compound were reported (0.11 to 17.2%). TMC435 metabolites in this matrix were formed mainly by hydroxylation and O-demethylation and also by glucuronidation.
The most important metabolic route TMC435 in rat and dog was O-demethylation of the parent drug to M18 (12.8%- 6.4% male-female rats; 18.8% dogs). In rats other metabolites were formed by oxidation of M18 and oxidation of unchanged drug. In dogs, further oxidation of M18 to M14 and M8, and of the unchanged drug to M21, M16 and M11 were also reported as minor routes. The human metabolism profile suggests that TMC435 is mainly metabolized by two main routes, (1) oxidation of unchanged drug, either at the macrocyclic moiety (M27, M21 and M22), or at the aromatic moiety (M26 and M16), or both (M23, M24, M25 and M11) and (2) the O-demethylation of unchanged drug to M18, followed by oxidation on the macrocyclic moiety to M14 and by oxidation on the aromatic moiety to M5, appears to be the secondary metabolic pathway in man. M21 and M22 were the most important metabolites in human faeces. Other relevant metabolites (1% of the dose) were M11, M16, M27 and M18. All metabolites detected in human feces were detected in vitro and/or in vivo in rat and/or dog feces. The main CYP enzymes involved in TMC435 metabolism were CYP3A enzymes although in vitro data suggests the involvement of CYP2C8 and CYP2C19.
In large randomized controlled trials, simeprevir was not linked to an increased rate of serum enzyme elevations during treatment or with instances of clinically apparent liver injury. Simeprevir causes a mild increase in serum indirect bilirubin and some patients became visibly jaundiced, but the bilirubin elevations were generally mild, transient and not associated with changes in serum aminotransferase or alkaline phosphatase levels. After its approval and more wide scale use, however, simeprevir has been implicated in at least one case of an acute hepatitis (Case 1). The latency to onset was 7 weeks and pattern of injury was hepatocellular without immunoallergic or autoimmune features. Recovery was rapid and complete once therapy was stopped.
In addition, simeprevir, in combination with other agents, has been linked to instances of acute, seemingly spontaneous decompensation of HCV related cirrhosis. The role of simeprevir as opposed to the other HCV antivirals used in combination was often unclear. Rates of hepatic decompensation during simeprevir combination therapy of cirrhosis due to hepatitis C was approximately 2% to 3% when combined with peginterferon and ribavirin, and 0.5% to 1.0% when used with sofosbuvir. Because of the risk of decompensation, patients with cirrhosis who are treated with antiviral regimens (both all-oral and interferon based) should be monitored for evidence of worsening liver disease, particularly during the first 4 weeks of treatment. This complication is probably more common in patients with more advanced liver disease, Child’s Class B cirrhosis and those with a previous history of liver decompensation.
Likelihood score: D (possible rare cause of clinically apparent liver injury in susceptible individuals).
Mechanism of Injury
The mechanism by which simeprevir might cause liver injury is not known. It is metabolized in the liver largely via the cytochrome P450 system, predominantly CYP 3A and it is an inhibitor of the drug transporters P-glycoprotein and OATP1Ba/3 and the efflux transporters MDR1, MRP2 and BSEP, perhaps accounting for the indirect hyperbilirubinemia that occurs in some patients. Simeprevir is associated with drug-drug interactions and it can raise levels of some statins. The decompensation that occurs with simeprevir combination therapy may be due to a direct effect of the agent, or else represent a usual complication of the rapid eradication of HCV infection. Finally, the episodes of decompensation may be incidental and unrelated to the antiviral therapy.
In vitro, simeprevir is a substrate and inhibitor of P-glycoprotein (P-gp) transport. Concomitant use of simeprevir with drugs that are P-gp substrates may result in increased concentrations of such drugs.
Pharmacokinetic interaction with cyclosporine (increased cyclosporine concentrations). Cyclosporine dosage adjustments are not needed when used concomitantly with simeprevir; routine monitoring of cyclosporine concentrations is recommended.
Concomitant use of simvastatin (single 40-mg dose) and simeprevir (150 mg once daily for 10 days) resulted in a 1.5-fold increase in simvastatin AUC due to inhibition of OATP1B1 and/or CYP3A4 by simeprevir. If simvastatin is used concomitantly with simeprevir, dosage of simvastatin should be titrated carefully and the lowest necessary dosage of simvastatin used; the patient should be monitored for safety.
Concomitant use of a rosuvastatin (single 10 mg dose) and simeprevir (150 mg once daily for 7 days) resulted in a 2.8-fold increase in rosuvastatin AUC due to inhibition of OATP1B1 by simeprevir. If rosuvastatin is used concomitantly with simeprevir, dosage of rosuvastatin should be initiated at 5 mg once daily and should not exceed 10 mg once daily.
Simeprevir is extensively bound to plasma proteins (greater than 99.9%), primarily to albumin and, to a lesser extent, alfa 1-acid glycoprotein. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.
Administration of simeprevir with food to healthy subjects increased the relative bioavailability (AUC) by 61% and 69% after a high-fat, high-caloric (928 kcal) and normal-caloric (533 kcal) breakfast, respectively, and delayed the absorption by 1 hour and 1.5 hours, respectively. Due to increased bioavailability, Olysio should be administered with food. The type of food does not affect exposure to simeprevir.
Elimination of simeprevir occurs via biliary excretion. Renal clearance plays an insignificant role in its elimination. Following a single oral administration of 200 mg (14)C-simeprevir to healthy subjects, on average 91% of the total radioactivity was recovered in feces. Less than 1% of the administered dose was recovered in urine. Unchanged simeprevir in feces accounted for on average 31% of the administered dose.
In animals, simeprevir is extensively distributed to gut and liver (liver:blood ratio of 29:1 in rat) tissues. In vitro data and physiologically-based pharmacokinetic modeling and simulations indicate that hepatic uptake in humans is mediated by OATP1B1/3.
Ring-Closing Metathesis on Commercial Scale: Synthesis of HCV Protease Inhibitor Simeprevir
摘要：
The key macrocyclization step in the synthesis of simeprevir, a hepatitis C virus (HCV) antiviral drug, was studied. N-Boc substitution on the diene precursor changes the site of insertion of the metathesis catalyst and, consequently, the kinetic model of the ring closing metathesis (RCM), enabling a further increase in the macrocyclization efficiency under simulated high dilution (SHD) conditions. NMR of the inserted species of both first and second generation RCM catalysts are reported and discussed.
This invention relates to combinations of therapeutic molecules useful for treating hepatitis C virus infection. The present invention relates to methods, uses, dosing regimens, and compositions.
这项发明涉及治疗丙型肝炎病毒感染的治疗分子组合。本发明涉及方法、用途、给药方案和组合物。
[EN] PROCESSES AND INTERMEDIATES FOR PREPARING A MACROCYCLIC PROTEASE INHIBITOR OF HCV<br/>[FR] PROCÉDÉS ET INTERMÉDIAIRES POUR LA PRÉPARATION D'UN INHIBITEUR DE PROTÉASE MACROCYCLIQUE DU VHC
申请人：JANSSEN PHARMACEUTICALS INC
公开号：WO2013041655A1
公开（公告）日：2013-03-28
Disclosed is a process for the preparation of a cinchonidine salt of formula (IV) via an aqueous solution of a racemic 4-hydroxy-1,2-cyclopentanedicarboxylic acid, which is subjected to cyclization without removing water, by the addition of a water- miscible organic solvent to the aqueous solution and, again without removing water, adding cinchonidine to the aqueous-organic solvent solution so as to obtain the cinchonidine salt of the lactone acid. The cinchonidine salt is allowd to crystallize so as to obtain the enantiomerically purified crystalline lactone acid cinchonidine salt (IV). The enantiomerically pure salt is an intermediate in the synthesis of HCV inhibitor compound of formula (I).
CYCLOPROPYLBORONIC COMPOUNDS, METHOD FOR PREPARING SAME AND USE THEREOF
申请人：DIVERCHIM
公开号：US20150329566A1
公开（公告）日：2015-11-19
Cyclopropylboronic compounds, the preparation process thereof and the use thereof.
环丙基硼化合物，其制备方法及用途。
[EN] PROCESSES AND INTERMEDIATES FOR PREPARING A MACROCYCLIC PROTEASE INHIBITOR OF HCV<br/>[FR] PROCÉDÉS ET INTERMÉDIAIRES POUR PRÉPARER UN INHIBITEUR MACROCYCLIQUE DE PROTÉASE DU VHC
申请人：ORTHO MCNEIL JANSSEN PHARM
公开号：WO2010072742A1
公开（公告）日：2010-07-01
The present invention relates to the cinchonidine salt useful in the preparation of intermediates for preparing a macrocyclic HCV inhibitor, as well as processes involving this salt.
本发明涉及可用于制备大环HCV抑制剂中间体的奎宁啶盐，以及涉及该盐的制备过程。
PROCESS FOR MAKING HCV PROTEASE INHIBITORS
申请人：ABBVIE INC.
公开号：US20130178630A1
公开（公告）日：2013-07-11
Efficient processes for making HCV protease inhibitors are described. In one embodiment, the process uses novel idazolide derivatives of vinyl-ACCA.
