A whole-body physiologically based pharmacokinetic (PBPK) model of elagolix was developed to quantitatively account for the contribution of metabolizing enzymes, transporters, and their interplay. |
The PBPK model was able to adequately describe clinical pharmacokinetics data and recover the observed drug–drug interaction (DDI), demonstrating that the model is verified for the intended purpose. |
Simulations using elagolix PBPK model informed labeling information regarding the DDI potential with digoxin (P-glycoprotein substrate) and midazolam (cytochrome P450 3A4 substrate) under dosing conditions that were not tested clinically. |
1 Introduction
2 Materials and Methods
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 |
2.1 Elagolix Physiologically Based Pharmacokinetic (PBPK) Model Development, Verification, and Application
2.2 Simulation Design
Pharmacokinetic parameter (units) | 150 mg QD (N = 6) | 200 mg BID (N = 7) | ||||
---|---|---|---|---|---|---|
Predicted | Observed | %PE | Predicted | Observed | %PE | |
Day 1 | ||||||
Cmax (ng/mL) | 524 | 507 | 3.4 | 779 | 712 | 9.4 |
Tmax (h) | 0.95 | 1.3 | 26.9 | 0.95 | 1.0 | 5.0 |
AUCτ (ng●h/mL)a | 1321 | 1331 | 0.8 | 1756 | 1813 | 3.1 |
Day 21 | ||||||
Cmax (ng/mL) | 524 | 574 | 3.4 | 680 | 774 | 12.1 |
AUCτ (ng●h/mL)a | 1213 | 1292 | 6.1 | 1518 | 1725 | 12 |
CL/F (L/h) | 124 | 123 | 1 | 132 | 144 | 8 |
t½ (h) | 4.57 | 6.42 | 28.8 | 4.54 | 4.29 | 5.8 |
2.3 PBPK Model Performance Evaluation
2.3.1 Prespecified Acceptance Criteria for Pharmacokinetic Parameters (Maximum Concentration [Cmax], Area Under the Concentration–Time Curve [AUC], and Half-Life)
2.3.2 Prespecified Acceptance Criteria for Drug–Drug Interaction (DDI) Studies and Hepatic Impairment Studies (Cmax Ratio and AUC Ratio)
3 Results
3.1 Development and Verification of the Elagolix PBPK Model Using a Combined Bottom-Up and Top-Down Approach
Elagolix dose, mg | Mean Cmax ratio | Mean AUC ratio | |||||
---|---|---|---|---|---|---|---|
Predicted | Observed | %PE | Predicted | Observed | %PE | ||
Coadministered drug with elagolix | DDI studies | ||||||
Rifampin day 1 | 150a | 3.20 | 4.37 | 27 | 4.00 | 5.58b | 28 |
Rifampin day 10 | 150a | 2.28 | 2.00 | 14 | 2.29 | 1.65b | 39 |
Ketoconazole | 150a | 2.01 | 1.77 | 14 | 2.13 | 2.20c | 3.2 |
Patient population | Hepatic impairment studies | ||||||
Child–Pugh A | 150a | 1.5 | 0.8 | 88 | 1.6 | 0.8c | 100 |
Child–Pugh B | 150a | 3.7 | 2.6 | 42 | 4.5 | 2.7c | 67 |
Child–Pugh C | 150a | 4.8 | 6.2 | − 23 | 7.3 | 6.7c | 9 |
3.2 PBPK Model of Elagolix as a Cytochrome P450 (CYP) 3A Inducer and P-Glygoprotein (P-gp) Inhibitor
Victim drug | Model stage | Elagolix dose | Mean Cmax ratio | Mean AUC∞ ratio | ||||
---|---|---|---|---|---|---|---|---|
Predicted | Observed | %PE (%) | Predicted | Observed | %PE (%) | |||
Midazolam | Development | 150 mg QD | 0.75 | 0.81 | 8 (77) | 0.69 | 0.65 | 6 (46) |
Application | 200 mg BID | 0.51 | Not applicable | 0.44 | Not applicable | |||
Digoxin, day 1 | Development | 200 mg BID | 1.74 | 1.73 | 0.6 (42) | 1.22 | 1.32 | 8 (24) |
Digoxin, day 10 | 200 mg BID | 1.73 | 1.71 | 1 (42) | 1.19 | 1.26 | 6 (21) | |
Digoxin, day 1 | Application | 150 mg QD | 1.68 | Not applicable | 1.19 | Not applicable | ||
Digoxin, day 10 | 150 mg QD | 1.73 | 1.19 |