Table 1.

Total and unbound concentrations of tyrosine kinase inhibitors that inhibit the proliferation of AML cell lines

Cell lineIC50 (μmol/L)
Imatinib (Css,ave,unbound = 0.29 μmol/L)
Sunitinib (Css,ave,unbound = 0.0084 μmol/L)
Sorafenib (Css,ave,unbound = 0.059 μmol/L)
TotalUnboundTotalUnboundTotalUnbound
HL-6029 ± 129.92.2 ± 0.600.863.3 ± 0.430.043
Kasumi-10.27 ± 0.0650.0920.023 ± 0.00500.0090.040 ± 0.0110.001
KG-117 ± 0.805.81.1 ± 0.160.432.7 ± 0.930.035
NB4>40>1413 ± 3.75.16.6 ± 0.780.086
ML-216 ± 7.85.43.3 ± 0.461.33.7 ± 0.700.048
MV4-11>20>6.80.007 ± 0.00030.0030.002 ± 0.00070.00003
THP-1>20>6.82.9 ± 0.651.16.2 ± 1.30.081
U93718 ± 2.96.16.2 ± 2.32.46.9 ± 0.540.090
M-07e>20>6.89.8 ± 2.23.89.1 ± 2.80.12
  • NOTE: Total IC50 are the mean ± SD of three independent experiments done in eight replicates. The unbound IC50 for inhibiting proliferation was estimated for each drug and cell line by multiplying the mean total IC50 by the unbound fraction in cell culture (34%, 39%, and 1.3%, for imatinib, sunitinib, and sorafenib, respectively). To relate unbound concentrations achieved clinically to unbound IC50 in vitro, Css,ave,unbound in human plasma was estimated by multiplying Css,ave,total (3 μmol/L, 100 nmol/L, and 10 μmol/L for imatinib, sunitinib, and sorafenib, respectively, at the approved adult doses of 400, 50, and 400 mg, respectively) by the % unbound fraction in plasma (9.5%, 8.4%, and 0.59% for imatinib, sunitinib, and sorafenib, respectively).