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

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 AUC(0-12) and C-max associated with a twofold increase in dose (AUC(0-12), 10.6 mu M/h to 59.5 mu M/h; C max, 2.60 mu M to 13.5 mu M). In the 300 mg and 600 mg dose groups, mean liver concentrations of vaniprevir were 84.6 mu M and 169 mu M at 6 h post-dose, and 29.4 mu M and 53.7 mu M 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.