title: Safety, pharmacokinetics and resistant variants of telaprevir alone for 12 weeks in hepatitis C virus genotype 1b infection.
abstract: BACKGROUND
  Telaprevir in combination with peginterferon and ribavirin is a promising advancement in chronic hepatitis C treatment. However, the safety, tolerability, pharmacokinetics and antiviral profiles of telaprevir alone beyond 2 weeks have not been studied.
  
  
  METHODS
  In a phase 1b study in Japan, 10 treatment-naïve patients infected with hepatitis C virus genotype 1b with high viral load (>5 log(10) IU/mL) received telaprevir 750 mg every 8 h (q8h) for 12 weeks. We examined the safety, tolerability, pharmacokinetics, hepatitis C virus (HCV) RNA levels and resistant variants of telaprevir.
  
  
  RESULTS
  Neither serious adverse events nor discontinuations of study drug owing to an adverse event occurred. The most common adverse drug reactions were rash (80%) and anaemia (70%). Telaprevir concentration reached its steady state within 2 days after the first administration without abnormal accumulation. Telaprevir alone provided potent antiviral activity: a median log(10) decrease of 2.325 at 16 h and 5.175 on Day 14. During the treatment, HCV RNA levels at the nadir were below the limit of the quantification in seven patients and undetectable in three of 10 patients. Viral breakthrough associated with mainly Ala(156) -substituted variants occurred in eight patients, and only one patient showed end-of-treatment response. The selected variants reverted to the wild-type during the 24-week follow-up period.
  
  
  CONCLUSIONS
  Telaprevir alone was well tolerated at 750 mg q8h for up to 12 weeks. The safety profile and emergence of resistant variants of genotype 1b under telaprevir monotherapy for 12 weeks will become increasingly important in evaluating an oral combination of telaprevir with other direct-acting antiviral agents.
authors.affiliation: Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan. Yamada.Ichimaro@mf.mt-pharma.co.jp
authors.forename: I
authors.initials: I
authors.lastname: Yamada
authors.forename: F
authors.initials: F
authors.lastname: Suzuki
authors.forename: N
authors.initials: N
authors.lastname: Kamiya
authors.forename: K
authors.initials: K
authors.lastname: Aoki
authors.forename: Y
authors.initials: Y
authors.lastname: Sakurai
authors.forename: M
authors.initials: M
authors.lastname: Kano
authors.forename: H
authors.initials: H
authors.lastname: Matsui
authors.forename: H
authors.initials: H
authors.lastname: Kumada
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification*; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D012367:RNA, Viral / Q000097:blood; D013997:Time Factors; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D009842:Oligopeptides; D012367:RNA, Viral; C486464:telaprevir