Table 1.

Input parameters of the elagolix PBPK model using SimCYP (V15.0.86.0)

Parameter	Parameter value used in the SimCYP model	Source
Physiochemical and blood binding
Molecular weight (g/mol)	631.6	Experimental data
logP	1.34
pKa 1	4
pKa 2	7.9
Blood-to-plasma ratio	0.62
fu	0.21
Absorption model	ADAM
Peff,man type	Regional
P Caco-2 (10−6 cm/s)	10	Estimated based on clinical data
Input form	Solution	Experimental data
Distribution model	Full PBPK model
Vss input type	Predicted using Method 2	SimCYP predicted
Elimination
CYP3A4 CLint (µL/min/pmol of isoform)	0.3	Estimated based on clinical data
CYP2C8 CLint (µL/min/pmol of isoform)	0.029	Experimental data
CYP2D6 CLint (µL/min/pmol of isoform)	0.7	Experimental data
CLrenal (L/h)	1.6	Estimated based on clinical data
Additional systemic CL/F (L/h)	9	Estimated based on clinical data
Transporter kinetics
P-gp
CLint (µL/min/pmol)	4	Estimated based on clinical data
OATP1B1
Jmax (pmol/min/million cells)	215	Estimated based on clinical data
Km (µM)	0.66	Experimental data
Perpetrator properties
CYP3A4 enzyme MBI
MBI Kapp (µM)	74	Experimental data
MBI Kinact (1/h)	0.019	Experimental data
CYP3A4 enzyme induction
Indmax	20	Experimental data
Ind EC50 (µM)	2	Estimated based on clinical data
P-gp inhibition Ki (µM)	0.5	Estimated based on clinical data

ADAM advanced dissolution, absorption, and metabolism, CL/F apparent clearance, CL_int intrinsic clearance, CL_renal renal clearance, CYP cytochrome P450, EC₅₀ half maximal effective concentration, fu fraction of unbound drug in plasma, Ind_max maximum induction, J_max maximal transport velocity, K_app apparent binding constant, K_i inhibitory constant, K_inact inactivation rate constant, K_m Michaelis–Menten constant, logP partition coefficient, MBI mechanism-based inactivation, OATP organic anion transporting polypeptide, PBPK physiologically based pharmacokinetic, P-gp P-glycoprotein, PK pharmacokinetic, pKa acid dissociation constant, V_ss volume of distribution at steady state