TABLE 1

Predicted CLint and CLh values and clinical reference data

In vitro half-life (t1/2) is expressed in [h]. Clearance values are expressed in [mL/min/kg] and refer to blood elimination. Data represent mean values ± S.D. obtained using hepatocyte spheroids from donors A, B, and C (apixaban, carbamazepine, clozapine, olanzapine) or mean values ± S.D. obtained using hepatocyte spheroids from donor C in two independent experiments (nortriptyline, risperidone, venlafaxine). Literature references for clinical CLh values are provided in Supplemental Table 2.

Observed CLhIndividual SpheroidsPooled Spheroids
t1/2CLintCLhPt1/2CLintCLhP
Apixaban0.5761003.1 ± 432.12.78 ± 1.470.434 ± 0.224<0.051463.7 ± 1202.60.244 ± 0.1580.0389 ± 0.0251<0.05
Carbamazepine0.1102149.2 ± 310.91.12 ± 0.1620.254 ± 0.0363N.S.1464.5 ± 1365.40.289 ± 0.2290.0661 ± 0.0524<0.05
Clozapine2.1983.4 ± 21.529.7 ± 6.691.64 ± 0.344<0.000113.7 ± 8.5221.5 ± 9.961.21 ± 0.537<0.0001
Olanzapine3.55196.4 ± 91.813.8 ± 5.521.28 ± 0.488<0.0590.0 ± 12.12.67 ± 0.3780.264 ± 0.0368<0.0001
Nortriptyline6.6827.0 ± 0.24787.9 ± 0.7993.00 ± 0.0234<0.0001
Risperidone7.7448.5 ± 2.6449.0 ± 2.915.59 ± 0.233<0.0001
Venlafaxine8.79135.1 ± 11.137.5 ± 0.7464.77 ± 0.244<0.0001