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. Author manuscript; available in PMC: 2021 Mar 10.
Published in final edited form as: Clin Pharmacol Ther. 2020 Sep 14;109(2):494–506. doi: 10.1002/cpt.2021

Table 3.

PBPK model-predicted unbound drug exposure in the plasma, normal brain, cranial CSF, and spinal CSF at the steady-state following the standard or modified dosing regimensa

Ribociclib Palbociclib Abemaciclib
Standard (600 mg QD, 21 days) Alternative (900 mg QD, 21 days) Standard (125 mg QD, 21 days) Alternative (187 mg QD, 21 days) Standard (150 mg BID, 28 days) Alternative (300 mg QD, 28 days)
Plasma
Tss,max (h) 1.32 1.32 3.84 3.84 2.91 3.84
Css,max (μmol/L) 0.298 0.448 0.038 0.057 0.055 0.062
Css,min (μmol/L) 0.092 0.139 0.022 0.033 0.045 0.040
Css,ave (μmol/L) 0.176 0.264 0.029 0.044 0.050 0.050
AUC24h (μmol/L*h) 4.291 6.440 0.779 1.167 1.683 1.326
Brain
Tss,max (h) 3.84 3.84 3.84 3.84 6.27 10.56
Css,max (μmol/L) 0.039 0.059 0.005 0.007 0.052 0.053
Css,min (μmol/L) 0.014 0.020 0.003 0.004 0.051 0.050
Css,ave (μmol/L) 0.024 0.036 0.004 0.005 0.052 0.052
AUC24h (μmol/L*h) 0.624 0.935 0.096 0.143 1.746 1.391
Brain Kp,uub 0.14 0.14 0.12 0.12 1.04 1.05
TER for CDK4c 2.4 3.6 0.36 0.45 26 26
TER for CDK6c 0.62 0.92 0.27 0.33 5.2 5.2
Cranial CSF
Tss,max (h) 1.32 1.32 3.84 3.84 6.27 10.56
Css,max (μmol/L) 0.475 0.713 0.068 0.102 0.039 0.040
Css,min (μmol/L) 0.149 0.223 0.038 0.058 0.038 0.036
Css,ave (μmol/L) 0.281 0.421 0.052 0.078 0.038 0.038
AUC24h (μmol/L*h) 6.890 10.33 1.385 2.078 1.311 1.045
CSF Kp,uud 1.60 1.60 1.78 1.78 0.78 0.79
Spinal CSF
Tss,max (h) 3.84 3.84 6.36 6.36 6.27 10.56
Css,max (μmol/L) 0.404 0.606 0.063 0.094 0.039 0.039
Css,min (μmol/L) 0.159 0.238 0.040 0.060 0.038 0.037
Css,ave (μmol/L) 0.263 0.394 0.051 0.076 0.038 0.038
AUC24h (μmol/L*h) 6.742 10.11 1.379 2.069 1.293 1.030
CSF Kp,uud 1.57 1.57 1.77 1.77 0.77 0.78
a

Simulations of 10 trials with 10 subjects in each trial were performed in the Simcyp cancer patient population. Data are presented as the population mean values.

b

Brain Kp,uu is estimated as the AUC24h ratio of unbound brain to unbound plasma at the steady-state.

c

TER (target engagement ratio) is calculated as the ratio of the average steady-state unbound brain concentrations to the in vitro IC50 for inhibiting CDK4/6 enzymes.

d

CSF Kp,uu is estimated as the AUC24h ratio of CSF to unbound plasma at the steady-state.

Abbreviations: Css,max, maximum steady-state concentration; Css,min, trough steady-state concentration; Css,ave, average steady-state concentration; AUC24h, area under the concentration time curve during 24 h at the steady-state.