Table 1.

Input parameters of dasatinib for PBPK model in Simcyp^® Simulator (v18.1)

Parameters	Value	Data source/comment
Physicochemical parameters
Molecular weight	488.01	Sprycel Package Insert [1]
LogP	3.20	Predicted in Simcyp® from LogD (4.27–3.23, pH 2–9)
pKa	3.1, 6.8	DCN950068845 (Supplementary Table 1)
Compound type	Diprotic base
Blood/plasma ratio	1.8	Kamath et al. 2008 [7]
fu in plasma	0.04	NDA clinical pharmacology summary
Absorption (ADAM model)
fa	0.9996	Predicted in Simcyp® from MechPeff model
ka (h−1)	4.226	Predicted in Simcyp® from MechPeff model
fuGut	0.04	fu in plasma
Effective human Pc (10−4 cm/s)	9.667	Predicted in Simcyp® from MechPeff model
Particle size (µm)	38 (average)	DCN950068845 (Supplementary Table 1); 50 mg tablet
Intrinsic solubility (mg/mL)	0.03	DCN950068845 (Supplementary Table 1); Bio-relevant solubility
Distribution (full PBPK model)
Kp scaler	0.7	Optimized to fit the observed PK profiles
Vss (L/kg)	5.2	Predicted using method 2 full PBPK model in Simcyp®
Elimination
CLpo (L/h)	338	Averaged from 4 studies (CA180009, CA180016, CA180032, and CA180249; BMS, Supplementary Table 1)
CYP3A4 CLint (µL/min/pmol CYP)	11.635	Predicted in Simcyp® retrograde when CYP3A4 accounts for 82.5% with fa of 0.8 (DCN930011322; Supplementary Table 1)
Renal clearance (L/h)	0.4	Human ADME CA180019 [3]
Additional HLM CLint (µL/min/mg protein)	319.32	Predicted in Simcyp® retrograde
Transportera	n.a
Interactionb,c
CYP3A4 Ki (µM)	9.0 (midazolam) 5.0 (testosterone)c,d	DCN930011322 (Supplementary Table 1)
CYP3A4 Kapp (µM)	1.9	DCN930011322 (Supplementary Table 1)
CYP3A4 Kinact (min−1)	0.022 (midazolam)	DCN930011322 (Supplementary Table 1)
CYP2C8 Ki (µM)	3.6	DCN930011322 (Supplementary Table 1)
OCT2 Ki (µM)	0.034	DCN930147497 (Supplementary Table 1)
MATE1 Ki (µM)	0.22
MATE2K Ki (µM)	0.86	DCN930147085 (Supplementary Table 1)
OATP1B1 Ki (µM)	9.2 (2.33)d	DCN930147497 (Pahwa et al. 2017 [16]; Supplementary Table 1)
OATP1B3 Ki (µM)	4.4 (2.75)d

ADAM advanced dissolution, absorption, and metabolism, ADME absorption, distribution, metabolism, and excretion, BCRP breast cancer resistance protein, BMS Bristol Myers Squibb, CLint intrinsic clearance, CLpo oral clearance, CYP cytochrome P450, f_a fraction absorbed, fu fraction unbound, fu_Gut fraction unbound in the gut, HLM human liver microsome, Kp partition coefficient, IC₅₀ half maximal inhibitory concentration, ka first-order absorption rate constant, K_app concentration of mechanism-based inhibition at 50% K_inact, K_i inhibitor constant, K_inact maximal inactivation rate, K_m amount of substrate needed to reach half of the maximum velocity of the reaction, MATE multidrug and toxin extrusion protein, MRP multidrug resistance-associated protein, n.a. not available, NDA new drug application, OAT organic anion transporter, OATP organic anion transporting polypeptide, OCT organic cation transporter, PBPK physiologically based pharmacokinetic, Pc permeability, P-gp P-glycoprotein, PK pharmacokinetic, pKa acid dissociation constant, S substrate concentration, Vss volume of distribution at steady state

^aThe in vitro information of dasatinib as transporter substrate was not available

^bExcept for CYP3A4 K_app and CYP3A4 K_inact, K_i was calculated from IC₅₀ using the equation for competitive inhibition (K_i = IC₅₀/[(S/K_m) + 1]

^cDasatinib was not expected to inhibit other CYP enzymes or transporters; the IC₅₀ values for other CYPs (CYP1A2, CYP2A6, CYP2B6, CYPC9, CYP2C19, CYP2D6, and CYP2E1) were ≥ 35 µM and values for other transporters (P-gp, BCRP, MRP2, MRP3, MRP4, OAT1, and OAT3) were ≥ 19.5 µM

^dWhen more than one K_i value was reported/listed, the model used the most potent value for a conservative approach, i.e., 5.0 (testosterone) versus 9.0 µM (midazolam) for CYP3A4; 2.33 and 2.75 versus 9.2 and 4.4 µM for OATP1B1 and OATP1B3, respectively