. 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 regimens ^a

	Ribociclib		Palbociclib		Abemaciclib
	Standard (600 mg q.d., 21 days)	Alternative (900 mg q.d., 21 days)	Standard (125 mg q.d., 21 days)	Alternative (187 mg q.d., 21 days)	Standard (150 mg b.i.d., 28 days)	Alternative (300 mg q.d., 28 days)
Plasma
T_ss,max, hours	1.32	1.32	3.84	3.84	2.91	3.84
C_ss,max, µmol/L	0.298	0.448	0.038	0.057	0.055	0.062
C_ss,min, µmol/L	0.092	0.139	0.022	0.033	0.045	0.040
C_ss,ave, µmol/L	0.176	0.264	0.029	0.044	0.050	0.050
AUC_24h, µmol/L*h	4.291	6.440	0.779	1.167	1.683	1.326
Brain
T_ss,max, hours	3.84	3.84	3.84	3.84	6.27	10.56
C_ss,max, µmol/L	0.039	0.059	0.005	0.007	0.052	0.053
C_ss,min, µmol/L	0.014	0.020	0.003	0.004	0.051	0.050
C_ss,ave, µmol/L	0.024	0.036	0.004	0.005	0.052	0.052
AUC_24h, µmol/L*h	0.624	0.935	0.096	0.143	1.746	1.391
Brain K _p,uu ^b	0.14	0.14	0.12	0.12	1.04	1.05
TER for CDK4 ^c	2.4	3.6	0.36	0.45	26	26
TER for CDK6 ^c	0.62	0.92	0.27	0.33	5.2	5.2
Cranial CSF
T_ss,max, hours	1.32	1.32	3.84	3.84	6.27	10.56
C_ss,max, µmol/L	0.475	0.713	0.068	0.102	0.039	0.040
C_ss,min, µmol/L	0.149	0.223	0.038	0.058	0.038	0.036
C_ss,ave, µmol/L	0.281	0.421	0.052	0.078	0.038	0.038
AUC_24h, µmol/L*h	6.890	10.33	1.385	2.078	1.311	1.045
CSF K _p,uu ^d	1.60	1.60	1.78	1.78	0.78	0.79
Spinal CSF
T_ss,max, hours	3.84	3.84	6.36	6.36	6.27	10.56
C_ss,max, µmol/L	0.404	0.606	0.063	0.094	0.039	0.039
C_ss,min, µmol/L	0.159	0.238	0.040	0.060	0.038	0.037
C_ss,ave, µmol/L	0.263	0.394	0.051	0.076	0.038	0.038
AUC_24h, µmol/L*h	6.742	10.11	1.379	2.069	1.293	1.030
CSF K _p,uu ^d	1.57	1.57	1.77	1.77	0.77	0.78

AUC_24h, area under the concentration time curve during 24 hours at the steady‐state; CDK, cyclin D‐cyclin dependent kinase; CSF, cerebrospinal fluid; C_ss,ave, average steady‐state concentration; C_ss,max, maximum steady‐state concentration; C_ss,min, trough steady‐state concentration; PBPK, physiologically‐based pharmacokinetic; TER, target engagement ratio.

^{^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 K _p,uu is estimated as the AUC_24h ratio of unbound brain to unbound plasma at the steady‐state.

^{^c}

TER 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 K _p,uu is estimated as the AUC_24h ratio of CSF to unbound plasma at the steady‐state.