Table 1.

Drug‐specific parameters in the whole‐body‐4Brain PBPK models

	Ribociclib	Palbociclib	Abemaciclib	Comments/reference
Physicochemical
MW, g/mol	434.6	447.5	506.6	PubChem
LogP	2.38	2.77	4.25	ChemAxon
PKa1, strongest acidic	11.59	11.34	10.27	ChemAxon
PKa2, strongest basic	8.87	8.86	7.94	ChemAxon
B/P	1.5	1.9	1.2	Investigator brochure
f u,p	0.125	0.126	0.06	Experimental determined
Absorption
Fa	0.9	0.5	0.6	Assigned
Ka	0.8	0.367	0.197	Observed
Lag time, hours	0.5	0.658	0.5	Observed
fugut	0.0061	0.007	0.004	Simcyp predicted
Q gut, L/h	9.61	14.48	11.08	Simcyp predicted
Distribution
V ss, L/kg	12.19	16.31	7.86	Predicted by Method 3, K p scalar of 1
Elimination
HLMs:
Vmax, pmol/min/mg	313.7	518.5	2003	Experimental determined from HLM
K m, µM	13.4	78.1	126.2	Experimental determined from HLM
CLint, µL/min/mg	23.4	6.64	15.9	Experimental determined from HLM
fuinc	0.35	0.2	0.2	Experimental determined from HLM
HIMs:
Vmax, pmol/min/mg	104.8	280.7	494.3	Experimental determined from HIM
K m, µM	28.8	70.4	115.1	Experimental determined from HIM
CLint, µL/min/mg	3.64	3.99	4.29	Experimental determined from HIM
fumic	0.35	0.2	0.2	Experimental determined
CLR, L/h	7.5	10.5	1.5	Assigned
4Brain model
BBB
PSB, L/h	135	307	25	Estimated by Eq. 1 a
fu,br	0.044	0.015	0.006	Experimental determined from patient brain tumor tissue
CLABCB1,vitro, µL/min/mg	21770	26160	800	Experimental determined Eq. 2 b
CLABCG2,vitro, µL/min/mg	0	8580	90	Experimental determined Eq. 2 b
ABCB1 RAF at BBB	87.3	87.3	87.3	Determined based on ABCB1 abundance in normal human brain microvessels by Eq. 3 c
ABCB1 RAF at BBB	5.88	5.88	5.88	Determined based on ABCB1 abundance in human glioblastoma microvessels by Eq. 3 c
ABCG2 RAF at BBB	125.3	125.3	125.3	Determined based on ABCG2 abundance in normal human brain microvessels by Eq. 3 c
ABCG2 RAF at BBB	55.47	55.47	55.47	Determined based on ABCG2 abundance in human glioblastoma microvessels by Eq. 3 c
Blood‐CSF barrier
PSC, L/h	67.5	150	13	Assumed to be half of PSB
fucsf	1	1	1	Assigned given low CSF protein concentration
CLABCB1,vitro, µL/min/mg	21770	26160	800	Experimental determined Eq. 2 b
ABCB1 RAF at BCCSF	8.7	8.7	8.7	Assigned and validated by observed ribociclib CSF data
Brain‐cranial CSF barrier
PSE, L/h	300	300	300	Assigned assuming no barrier function

BBB, blood‐brain barrier; B/P, blood‐to‐plasma partition ratio; CL_ABCB1,vitro and CL_ABCB1,vitro, ABCB1‐mediated and ABCG2‐mediated in vitro efflux clearance, respectively; CL_int, in vitro intrinsic metabolic clearance; CL_R, renal clearance; f _u,br, fraction unbound drug in brain tissue; f _u,p, fraction of unbound drug in plasma; fu_csf, fraction unbound in cerebrospinal fluid; fu_gut, fraction of unbound drug in enterocytes; fu_mic, fraction of unbound in microsomal incubation; K _m, substrate concentration at which half of V_max is achieved; logP, logarithm of the neutral species octanol‐to‐buffer partition ratio; MW, molecule weight; PK_a, acid dissociation constant; PBPK, physiologically‐based pharmacokinetic; PSB, passive permeability‐surface area product at the BBB; PSC, passive permeability‐surface area product at the blood‐cranial CSF barrier; PSE, passive permeability‐surface area product at the brain‐cranial CSF barrier; Q _gut, gut blood flow; RAF, in vivo‐in vitro relative activity factor; V_max, maximum metabolic rate; V _ss, volume of distribution at steady‐state.

^a $\text{PSB}=\frac{P_{\text{app,A-B}}\times \text{SA}}{\lambda }$ (Eq. 1), where P _app,A→B is the apparent permeability determined from MDCKII cell monolayer; SA is the human brain microvasculature surface area (mean, 20 m²); and λ is unionization efficiency.

^b ${\text{CL}}_{\text{efflux,vitro}}=\frac{2\times P_{\text{app,A-B}}\times \left(\text{NER}‐1\right)\times \text{SA}}{\lambda \times {\text{Pro}}_{\text{cell}}}$ (Eq. 2), where CL_efflux,vitro (µL/min/mg) is the in vitro efflux transporter‐mediated intrinsic clearance; NER is the net efflux ratio determined from MDCKII‐ABCB1or MDCKII–ABCG2; P _app,A‐B is the apparent passive permeability determined from MDCKII; SA is the filter surface area (0.143 cm²) in a 96‐well transwell; λ is unionization efficiency; and Pro_cell is the cell membrane protein amount in a 96‐well transwell.

^c $\text{RAF}=\frac{\text{Abundance in vivo}}{\text{Abundance in vitro}}\times \text{BMvPGB}\times \text{BW}$ (Eq. 3), where RAF is the relative activity factor; BMvPGB is the milligrams of brain microvessels per gram brain; BW is the average human brain weight; abundance in vivo or in vitro represents the ABCB1/ABCG2 transporter protein expression level in human brain microvessels or in MDCKII‐ABCB1 and –ABCG2 cells, respectively.