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.

Paritaprevir and Ritonavir Liver Concentrations in Rats as Assessed by Different Liver Sampling Techniques

“…In this study, we assessed rat plasma and liver concentrations of paritaprevir and ritonavir by utilizing samples obtained by tissue resection, biopsy, and fine-needle aspiration. As anticipated from previous animal studies with ritonavir and the clinical data for the protease inhibitor vaniprevir, we found that both drugs were highly concentrated within the liver compared to plasma (3,11,20). Their liver concentrations, however, differed by tissue sample type, with the highest concentrations obtained for resection samples, followed by CNB, FNA 5 , FNA 3 , and FNA 1 samples.…”

“…It also permitted development of a normalization procedure to determine the percentage of liver contained within the sample through the identification of liver-enriched genes (21). As a follow-up to the initial study, we conducted two studies investigating liver-to-plasma drug concentration ratios (10,11). In the first, we performed CNB on three patients treated with vaniprevir and demonstrated higher human liver concentrations than the concentrations in plasma (11).…”

“…As a follow-up to the initial study, we conducted two studies investigating liver-to-plasma drug concentration ratios (10,11). In the first, we performed CNB on three patients treated with vaniprevir and demonstrated higher human liver concentrations than the concentrations in plasma (11). In the second study, we performed serial FNA procedures on 15 patients treated with telaprevir, pegylated interferon, and ribavirin.…”

“…DAAs, drugs which target the hepatocyte and whose liver concentration has been shown to vary considerably, can be used to examine factors that affect liver drug accumulation and the resultant pharmacodynamic effect, as assessed by sampling HCV RNA levels (10,11,18). Few studies, however, have measured DAA concentrations within the liver, largely because of the need for invasive sampling techniques, i.e., biopsy or surgical resection, and the difficulty in interpretation of liver drug concentration measurements compared to measurements made with traditional matrices (i.e., plasma, blood, and urine) (19).…”

“…Our group recently pioneered techniques for serial liver drug concentration assessments in vivo by using different methods of liver sample collection (10)(11)(12). While core needle biopsy (CNB) and fine-needle aspiration (FNA) are techniques that have been used for the past half century to obtain liver specimens during the clinical evaluation of patients with liver disease, a comparison of different sampling techniques for measurement of liver drug concentrations has not been performed previously (13)(14)(15)(16)(17).…”