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 hyper
