TABLE 4

Summary of CLh predictions for 17 compounds using HepatoPac incubations from three donors

CompoundIn Vivo CLnonrenalIn Vitro Predicted CLh from Three Donors
Donor RTMDonor 1Donor 3Mean ± SD
fuw/o fufuw/o fufuw/o fufuw/o fu
ml/min per kg
Low clearancea
 Warfarin0.0810.0423.490.0262.290.0403.360.036 ± 0.0093.05 ± 0.66
 Meloxicam0.120.0495.640.0192.700.0121.840.027 ± 0.0203.80 ± 2.34
 Tolbutamide0.310.395.120.232.550.253.600.29 ± 0.093.76 ± 1.29
 Diazepam0.530.218.540.197.980.156.660.18 ± 0.0317.73 ± 0.97
 Alprazolam0.611.434.190.7842.471.093.331.10 ± 0.323.33 ± 0.86
 Glimepiride1.120.59017.90.3616.30.2414.60.40 ± 0.1816.27 ± 1.65
 Theophylline1.131.132.481.152.591.483.291.25 ± 0.202.79 ± 0.44
 Prednisolone1.441.805.391.264.022.005.881.69 ± 0.385.10 ± 0.96
 Riluzole2.053.1318.83.0918.80.8114.12.35 ± 1.3317.23 ± 2.71
 Voriconazole3.805.929.927.9912.57.5712.037.16 ± 1.111.48 ± 1.37
 Within 2-fold (%)700500600600
 Within 3-fold (%)10020702070109010
Intermediate clearanceb
 Risperidone5.164.2514.65.1515.71.568.813.65 ± 1.8713.0 ± 3.7
 Flecainide5.821.312.990.9502.270.6211.520.96 ± 0.342.26 ± 0.74
 Atomoxetinec7.052.0018.61.4917.90.3712.11.29 ± 0.8316.2 ± 3.6
 Diclofenac7.671.9920.01.1619.31.0519.21.40 ± 0.5119.6 ± 0.44
 Atazanavir8.1312.319.110.418.48.8517.610.5 ± 1.718.3 ± 0.6
 Midazolam8.59NDND4.5219.64.5219.34.5219.3
 Lidocaine10.77.2713.36.2712.35.1010.96.21 ± 1.0912.2 ± 1.21
 Within 2-fold (%)5033571443435714
 Within 3-fold (%)501005786437157100
  • ND, not determined.

  • a Low clearance is CLnonrenal <5 ml/min per kg.

  • b Intermediate clearance is 5 ml/min per kg < CLnonrenal <15 ml/min per kg.

  • c The in vivo clearance value reported for extensive metabolizers was used since the incidence of phenotype is highest in the population. Predicted CLh values for both corrected (CLh,w/fu) and not corrected (CLh, w/o/fu) plasma protein binding were derived from the average of at least two replicates. Categorization of fold prediction was defined as follows: for ±2-fold, 0.45 ≤ value ≤2.1; ±3-fold, 0.325 ≤ value ≤3.1.