Liver-to-plasma vaniprevir (MK-7009) concentration ratios in HCV-infected patients

Antivir Ther. 2015;20(8):843-8. doi: 10.3851/IMP2958. Epub 2015 Apr 7.

Abstract

Background: Some drugs that are actively taken up into the liver exhibit greater than dose proportional increases in plasma exposure, although human liver-to-plasma concentration ratios have rarely been evaluated. Understanding these relationships has implications for drug concentrations at the target site for certain classes of compounds, such as direct-acting antivirals, targeted towards HCV.

Methods: Treatment-experienced, chronic HCV non-cirrhotic patients (n=3) received vaniprevir (600 mg or 300 mg twice daily) on days 1-3 and (600 mg or 300 mg single dose) on day 4. Core needle biopsy was performed at 6 or 12 h post-dose on day 4. Blood samples were collected pre-dose on days 1 and 4, and for 24 h post-dose on day 4. The primary study objective was the hepatic concentration of vaniprevir at 6 and 12 h post-dose.

Results: Vaniprevir plasma pharmacokinetic parameters increased in a greater than dose-proportional manner between the 300 mg and 600 mg doses, with approximately fivefold increases in AUC0-12 and Cmax associated with a twofold increase in dose (AUC0-12, 10.6 μM/h to 59.5 μM/h; Cmax, 2.60 μM to 13.5 μM). In the 300 mg and 600 mg dose groups, mean liver concentrations of vaniprevir were 84.6 μM and 169 μM at 6 h post-dose, and 29.4 μM and 53.7 μM at 12 h post-dose. Liver concentrations were higher than plasma with liver-to-plasma concentration ratios of approximately 20-280.

Conclusions: These data confirm higher vaniprevir concentrations in human liver compared with plasma and demonstrate that measurement of human liver drug concentration using needle biopsy is feasible.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Antiviral Agents / administration & dosage*
  • Antiviral Agents / pharmacokinetics*
  • Biopsy
  • Cyclopropanes
  • Drug Monitoring
  • Female
  • Hepacivirus* / genetics
  • Hepatitis C, Chronic / complications
  • Hepatitis C, Chronic / diagnosis
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / virology*
  • Humans
  • Indoles / administration & dosage*
  • Indoles / pharmacokinetics*
  • Isoindoles
  • Lactams, Macrocyclic
  • Leucine / analogs & derivatives
  • Liver / metabolism*
  • Liver / pathology
  • Liver / virology*
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / pathology
  • Male
  • Middle Aged
  • Proline / analogs & derivatives
  • Sulfonamides

Substances

  • Antiviral Agents
  • Cyclopropanes
  • Indoles
  • Isoindoles
  • Lactams, Macrocyclic
  • Sulfonamides
  • Proline
  • vaniprevir
  • Leucine