TABLE 3

Pharmacokinetic properties of NVR 3-778 in PHHs cultured in HCM spiked with or without plasma proteins

ConditionMean value ± SEM (fold change)a
CLint,app (μl/min/106 cells)CLint,u (μl/min/106 cells)AUClast (ng · h/ml)Cavg (μM)KpDrug concn in liver/drug concn in mediumb
no BSA, no hA1GP89.49 ± 5.33122.75 ± 7.328,2480.26175.89 ± 14.9047.12 ± 0.61
4.3% BSA + 0.07% hA1GP15.77 ± 0.45 (5.7)162.56 ± 4.61 (1.3)24,749 (3.0)0.79 (3.0)30.96 ± 2.02 (5.7)8.29 ± 0.20 (5.7)
8% BSA + 0.07% hA1GP10.77 ± 0.14 (8.3)168.33 ± 2.22 (1.4)26,146 (3.2)0.84 (3.2)19.26 ± 1.58 (9.1)5.16 ± 0.05 (9.1)
  • a After 5 days of culturing, mock-infected PHHs were incubated with 1 μM NVR 3-778 for 4 days. Cells and supernatant were collected after 1, 24, 48, and 72 h to quantify turnover of the parent drug. Fold changes were calculated based on pharmacokinetic results obtained in PHHs cultured in HCM without BSA and hA1GP. CLint,app, intrinsic apparent clearance; CLint,u, unbound intrinsic clearance; AUClast, area under the concentration-time curve from time zero to the last measurable concentration; Cavg, average concentration; Kp, partition coefficient. Data represent mean values of three replicates ± SEM.

  • b Ratio of the predicted concentration of NVR 3-778 per gram of liver tissue (nanograms/gram of liver tissue) to the concentration of NVR 3-778 in the medium (nanograms/milliliter), normalized for hepatocellularity.