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 hepatitis C virus.

METHODS:

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

RESULTS:

Vaniprevir plasma pharmacokinetic parameters increased in a greater than dose-proportional manner between the 300-mg and 600-mg doses, with ~5-fold increases in AUC0-12 and Cmax associated with a 2-fold 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 hours post-dose, and 29.4 µM and 53.7 µM at 12 hours post-dose. Liver concentrations were higher than plasma with liver-to-plasma concentration ratios of ~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.
PMID: 25849338 [PubMed - as supplied by publisher]