Table 2.
Summary of predicted and observed AUC and Cmax ratios using minimal and full PBPK models for naloxegol 25 mg with coadministration of various CYP3A/P‐gp modulatorsa
| AUC | Cmax | ||||||
|---|---|---|---|---|---|---|---|
| Modulator | Dosing regimenb | Observed | Minimal PBPK model | Full PBPK model | Observed | Minimal PBPK model | Full PBPK model |
| Ketoconazole (CYP3A/P‐gp inhibitor) | 400 mg q.d. for 5 days (day 4) | 12.85 (11.3, 14.6) | 13.14 (11.9, 14.5) | 8.82 (7.17, 10.9) | 9.58 (8.1, 11.3) | 7.75 (6.9, 8.6) | 4.19 (3.38, 5.21) |
| Diltiazem (CYP3A/P‐gp inhibitor) | 240 mg q.d. for 5 days (day 4) | 3.41 (3.16, 3.68) | 2.80 (2.64, 2.98) | 2.45 (2.10, 2.86) | 2.85 (2.59, 3.14) | 2.28 (2.18, 2.39) | 1.70 (1.57, 1.83) |
| Rifampin (CYP3A/P‐gp inducer) | 600 mg q.d. for 10 days (day 10) | 0.11 (0.10, 0.13) | 0.24 (0.22, 0.26) | 0.37 (0.31, 0.43) | 0.25 (0.19, 0.31) | 0.27 (0.25, 0.30) | 0.35 (0.32, 0.39) |
| Quinidine (CYP3A/P‐gp inhibitor) | 600 mg single dose (day 1) | 1.38 (1.31, 1.46) | 1.13 (1.126, 1.14) | 1.23 (1.21, 1.25) | 2.44 (2.17, 2.75) | 1.19 (1.18, 1.21) | 1.87 (1.81, 1.93) |
AUC, area under the curve; Cmax, maximum concentration; CYP3A4, cytochrome P450 3A4; PBPK, physiologically based pharmacokinetic; P‐gp, p‐glycoprotein; q.d., once daily.
a
Data are geometric means with 90% confidence intervals.
b
Dosing regimen of modulator, with day of naloxegol 25 mg coadministration in parentheses.