Table 2.
Summary of naldemedine pharmacokinetic parameters when coadministered with a P-gp inhibitor, CYP3A inhibitors, or a CYP3A inducer and when administered alone
| Parameter | Cmax (ng/mL) | Tmax (h)a | AUC0–last (ng·h/mL) | AUC0–inf (ng·h/mL) | λz (1/h) | t1/2,z (h) | CL/F (L/h) |
|---|---|---|---|---|---|---|---|
| P-gp inhibitor study (n = 13) | |||||||
| Mean (SD) | |||||||
| Naldemedine + cyclosporine | 7.23 (1.84) | 1.00 (0.50–5.00) | 70.31 (12.98) | 70.70 (13.06) | 0.0786 (0.0103) | 8.96 (1.22) | 5.85 (1.16) |
| Naldemedine | 4.90 (0.69) | 0.75 (0.50–1.00) | 39.11 (6.46) | 39.46 (6.52) | 0.0655 (0.0078) | 10.7 (1.4) | 10.4 (1.84) |
| Geometric mean (CV %) | |||||||
| Naldemedine + cyclosporine | 7.03 (25.0) | 69.17 (19.2) | 69.55 (19.2) | 0.0780 (13.3) | 8.89 (13.4) | 5.75 (19.2) | |
| 38.60 (17.2) | 38.94 (17.3) | 0.0651 (12.5) | 10.6 (12.6) | 10.3 (17.3) | |||
| Naldemedine | 4.86 (14.5) | ||||||
| CYP3A inhibitors study (n = 14 in each cohort) | |||||||
| Cohort 1 | |||||||
| Mean (SD) | |||||||
| Naldemedine + itraconazole | 4.08 (0.868) | 1.00 (0.50, 4.00) | 74.31 (22.17) | 82.59 (24.83) | 0.0317 (0.0055) | 22.5 (3.98) | 2.70 (1.12) |
| Naldemedine | 3.77 (1.22) | 0.75 (0.50, 1.50) | 28.08 (7.300) | 28.31 (7.309) | 0.0684 (0.0173) | 10.7 (2.49) | 8.03 (4.39) |
| Geometric mean (CV %) | |||||||
| Naldemedine + itraconazole | 4.00 (20.2) | 70.88 (34.4) | 78.64 (35.3) | 0.0313 (17.8) | 22.2 (17.8) | 2.54 (35.3) | |
| Naldemedine | 3.56 (38.2) | 26.73 (38.2) | 26.98 (37.7) | 0.0665 (24.8) | 10.4 (24.8) | 7.41 (37.7) | |
| Cohort 2 | |||||||
| Mean (SD) | |||||||
| Naldemedine + fluconazole | 4.87 (0.784) | 1.00 (0.50, 2.50) | 51.00 (6.757) | 52.04 (6.976) | 0.0500 (0.0064) | 14.1 (1.86) | 3.91 (0.528) |
| Naldemedine | 3.57 (0.874) | 1.00 (0.50, 3.00) | 27.28 (4.739) | 27.53 (4.772) | 0.0702 (0.0170) | 10.4 (2.44) | 7.45 (1.16) |
| Geometric mean (CV %) | |||||||
| Naldemedine + fluconazole | 4.81 (16.1) | 50.58 (13.3) | 51.60 (13.5) | 0.0497 (13.1) | 14.0 (13.1) | 3.88 (13.5) | |
| Naldemedine | 3.48 (23.7) | 26.93 (16.5) | 27.18 (16.5) | 0.0683 (24.2) | 10.1 (24.2) | 7.36 (16.5) | |
| CYP3A inducer study (n = 14) | |||||||
| Mean (SD) | |||||||
| Naldemedine + rifampin | 1.72 (0.370) | 0.51 (0.50, 1.00) | 3.595 (0.616) | 3.745 (0.613) | 0.2174 (0.0304) | 3.26 (0.55) | 54.7 (8.42) |
| Naldemedine | 2.80 (0.666) | 1.00 (0.50, 2.50) | 21.84 (4.013) | 22.14 (4.121) | 0.0601 (0.0123) | 11.9 (1.98) | 9.35 (1.86) |
| Geometric mean (CV %) | |||||||
| Naldemedine + rifampin | 1.68 (21.1) | 3.549 (16.6) | 3.701 (16.0) | 0.2152 (15.5) | 3.22 (15.5) | 54.0 (16.0) | |
| Naldemedine | 2.72 (25.7) | 21.49 (19.1) | 21.77 (19.2) | 0.0591 (18.5) | 11.7 (18.5) | 9.19 (19.2) | |
AUC0–inf area under the concentration-time curve from 0 to infinity, AUC0–last area under the concentration-time curve from 0 to the last measurable concentration, CL/F apparent total clearance, Cmax maximum observed plasma concentration, CYP3A cytochrome P450 3A, CV coefficient of variation, λz apparent elimination rate constant, P-gp P-glycoprotein, SD standard deviation, t1/2,z apparent terminal elimination half-life, Tmax time to Cmax
aMedian (range)