title: Liver-to-plasma vaniprevir (MK-7009) concentration ratios in HCV-infected patients.
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.
authors: Merck and Company, Whitehouse Station, NJ, USA.
authors: D Hamish
authors: DH
authors: Wright
authors: Luzelena
authors: L
authors: Caro
authors: Michael
authors: M
authors: Cerra
authors: Paul
authors: P
authors: Panorchan
authors: Lihong
authors: L
authors: Du
authors: Melanie
authors: M
authors: Anderson
authors: Andrej
authors: A
authors: Potthoff
authors: Robert B
authors: RB
authors: Nachbar
authors: John
authors: J
authors: Wagner
authors: Michael P
authors: MP
authors: Manns
authors: Andrew H
authors: AH
authors: Talal
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001706:Biopsy; D003521:Cyclopropanes; D016903:Drug Monitoring; D005260:Female; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D007930:Leucine / Q000031:analogs & derivatives; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D008103:Liver Cirrhosis / Q000209:etiology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D013449:Sulfonamides
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D007211:Indoles; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D013449:Sulfonamides; D011392:Proline; C540393:vaniprevir; D007930:Leucine