Table 2.

Final input parameters for the zanubrutinib PBPK model

Parameter	Value	Source
Physicochemical properties
MW (g/mol)	471.55	Internal data
logP	4.2	Monoprotic base, experimental data a
pKa	3.3	Monoprotic base, experimental data a
B/P	0.804	Experimental data a
f u	0.0582	Experimental data a
Human absorption, dissolution, metabolism, and elimination
Peff,man (10−4 cm/s)	0.9	Experimental data a Adjusted to match Fa~0.7 based on clinical data
Qgut	5.9	Predicted by Simcyp
Solubility (mg/mL)	0.247, 0.073, 0.054, and 0.052 at pH 1.2, 4.5, 6.8, and 7.4, respectively	Experimental data a
CLin (L/h)	188.19	Adjusted by comparing time‐concentration profile of zanubrutinib 20 mg
CLout (L/h)	142.15	Adjusted by comparing time‐concentration profile of zanubrutinib 20 mg
Vss (L/kg)	9.4	Predicted by Simcyp Method 1
Vsac (L/kg)	9.2	Adjusted by comparing time‐concentration profile of zanubrutinib 20 mg
CLint (μL/min/mg)	120	Adjusted; A well‐stirred liver model for IVIVE CLint from HLM is 109 μL/min/mg a Estimated fmCYP3A4 is 81.6%
Additional clearance HLM (μL/min/mg)	60	Adjusted by comparing with the observed DDI data with itraconazole in study BGB−3111–104 4
fu,mic	0.407	Predicted (pH=7.4, microsomal protein 0.5 mg/mL)
CLR (L/h)	0.5	Based on human absorption, metabolism, and excretion study (BGB−3111–105); Estimated renal contribution: 1.6% of total CL
Drug interaction: induction/inhibition
Induction/suppression	CYP3A4: Indmax=6.27, IndC50=0.47 CYP2B6: Indmax=2.21, IndC50=0.73 CYP2C8: Indmax=4.172, IndC50=0.53 CYP2C9: Indmax=1.694, IndC50=0.119 CYP2C19: Indmax=2.02, IndC50=0.155	Estimated by the Emax model based on experimental data a Zanubrutinib at 0.3, 3, and 30 μM increased CYP3A4 activity by 2.02, 6.27, and 2.51‐fold, respectively Zanubrutinib at 0.3, 3, and 30 μM increased CYP2B6 mRNA levels by 1.6, 3.6, and 2.6‐fold, respectively Zanubrutinib at 0.3, 3, and 30 μM increased CYP2C8 activity by 1.39, 3.78, and 3.94‐fold, respectively Zanubrutinib at 0.3, 3, and 30 μM increased CYP2C9 activity by 1.21, 1.65, and 1.67‐fold, respectively. Zanubrutinib at 0.3, 3, and 30 μM increased CYC2C19 activity by 1.31, 2.04, and 1.91‐fold, respectively
Competitive inhibition	KiCYP1A2=60.5 μM KiCYP2B6=60.5 μM KiCYP2C8=2.015 μM KiCYP2C9=2.845 μM KiCYP2C19=3.790 μM KiCYP2D6=36.45 μM KiCYP3A4=7.15 μM	Experimental data a For a competitive enzyme inhibition, Ki calculated by Ki=IC50/2 Fraction unbound in microsomes, fu, mic=0.774 (predicted by microsomal protein: 0.1 mg/mL)

Abbreviations: B/P, blood/plasma partition ratio; CL_in and CL_out, clearance from the systemic compartment to the single‐adjusted compartment and from the single‐adjusted compartment to the systemic compartment, respectively; CL_int, intrinsic clearance; CL_R, renal clearance; CYP, cytochrome P450; f_a, fraction absorbed; fm_CYP3A4, fraction of drug metabolized by CYP3A4; f_u, fraction of unbound drug in plasma; f_u,mic, microsomal protein binding; HLM, human liver microsomes; Ind_C50, calibrated inducer concentration that supports half maximal induction (μM); Ind_max, calibrated maximal fold induction over vehicle (1= no induction); IVIVE, in vitro–in vivo extrapolation; ka, absorption rate constant; Ki, enzyme inhibition constant (concentration of inhibitor associated with half maximal inhibition); logP, Log of the octanol‐water partition coefficient for the neutral compound; MW, molecular weight; PBPK, physiologically based pharmacokinetics; P_{eff, man}, effective human jejunum permeability; PK, pharmacokinetics; pKa, acid dissociation constant; Q_gut, flow rate for overall delivery of drug to the gut (drug dependent); SAC, single adjusting compartment; V_max maximum velocity; V_sac, volume of the single adjusted compartment; V_ss volume of distribution at steady state.

^aInternal data.