indication

Treating chronic hepatitis C virus infection in certain patients. It must be used in combination with peginterferon and ribavirin.

pharmacology

Telaprevir is a direct-acting antiviral agent (DAA) against the hepatitis C virus.

mechanism of action

Telaprevir is an inhibitor of the HCV NS3/4A serine protease, necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins and essential for viral replication. In a biochemical assay, telaprevir inhibited the proteolytic activity of the recombinant HCV NS3 protease domain with an IC50 value of 10 nM.

toxicity

The highest documented dose administered is 1875 mg every 8 hours for 4 days in healthy subjects with telaprevir alone. In that study, the following common adverse events were reported more frequently with the 1875 mg q8h regimen compared to the 750 mg q8h regimen: nausea, headache, diarrhea, decreased appetite, dysgeusia, and vomiting.

biotransformation

Telaprevir is extensively metabolized in the liver, involving hydrolysis, oxidation, and reduction. Multiple metabolites were detected in feces, plasma, and urine. After repeated-oral administration, the R-diastereomer of telaprevir (30-fold less active), pyrazinoic acid, and a metabolite that underwent reduction at the α-ketoamide bond of telaprevir (not active) were found to be the predominant metabolites of telaprevir. In vitro studies using recombinant human cytochrome P450 (CYP) isoforms indicated that CYP3A4 was the major CYP isoform responsible for telaprevir metabolism. However, non-CYP mediated metabolism likely plays a role after multiple dosing of telaprevir.

absorption

Telaprevir is orally available, most likely absorbed in the small intestine, with no evidence for absorption in the colon. Maximum plasma concentrations after a single dose of telaprevir are generally achieved after 4 to 5 hours. In vitro studies performed with human Caco-2 cells indicated that telaprevir is a substrate of P-glycoprotein (P-gp). Exposure to telaprevir is higher during co-administration of peginterferon alfa and ribavirin than after administration of telaprevir alone.

half life

The mean elimination half-life after single-dose oral administration of telaprevir 750 mg typically ranged from about 4.0 to 4.7 hours. At steady state, the effective half-life is about 9 to 11 hours.

route of elimination

Following administration of a single oral dose of 750 mg 14C-telaprevir in healthy subjects, 90% of total radioactivity was recovered in feces, urine and expired air within 96 hours post-dose. The median recovery of the administered radioactive dose was approximately 82% in the feces, 9% in exhaled air and 1% in urine. The contribution of unchanged 14C-telaprevir and the R-diastereomer of telaprevir towards total radioactivity recovered in feces was 31.9% and 18.8%, respectively.

drug interactions

Clobetasol: Corticosteroids such as clobetasol may decrease the serum concentration of telaprevir. Telaprevir may increase the serum concentration of corticosteroids. Concurrent use of telaprevir and systemic corticosteroids is not recommended. When possible, consider alternatives, and if such a combination is necessary, use extra caution, monitoring patients for excessive systemic steroid effects as well as for diminished telaprevir effects.

Clocortolone: Corticosteroids such as clocortolone may decrease the serum concentration of telaprevir. Telaprevir may increase the serum concentration of Corticosteroids. Concurrent use of telaprevir and systemic corticosteroids is not recommended. When possible, consider alternatives, and if such a combination is necessary, use extra caution, monitoring patients for excessive systemic steroid effects as well as for diminished telaprevir effects.