TABLE 3.
Remibrutinib pharmacokinetics after single or multiple oral administration of 100 mg remibrutinib (with TMDD) with CYP3A4 inhibitors or inducers
| Perpetrator, schedule | Perpetrator present | Remibrutinib | Predicted Cmax (ng/ml) | Predicted AUC (ng*h/ml) | Cmax ratio | AUC ratio |
|---|---|---|---|---|---|---|
| Ritonavir, 100 mg b.i.d. |
No Yes |
20 mg s.d. p.o. |
30.8 (28.5–3.3) 105 (99.1–112) |
70.2 (64.8–76.0) 300 (282–318) |
3.41 (3.22–3.62) | 4.27 (4.00–4.55) |
| Ritonavir, 100 mg b.i.d. |
No Yes |
20 mg s.d. i.v. |
1089 (960–1234) 1056 (935–1193) |
286 (277–295) 435 (416–455) |
0.97 (0.97–0.97) | 1.51 (1.48–1.56) |
| Ketoconazole, 200 mg b.i.d. |
No Yes |
100 mg s.d. p.o. |
136 (125–148) 542 (515–570) |
329 (304–357) 1522 (1452–1596) |
3.98 (3.72–4.26) |
4.62 (4.32–4.94) |
| Ketoconazole, 200 mg b.i.d. |
No Yes |
100 mg q.d. p.o. |
188 (176–202) 648 (620–678) |
432 (402–465) 1803 (1723–1887) |
3.44 (3.24–3.66) | 4.17 (3.90–4.46) |
| Erythromycin, 500 mg b.i.d. |
No Yes |
100 mg s.d. p.o. |
136 (125–148) 343 (323–365) |
329 (304–357) 893 (842–947) |
2.52 (2.38–2.67) | 2.71 (2.56–2.87) |
| Erythromycin, 500 mg b.i.d. |
No Yes |
100 mg q.d. p.o. |
188 (176–202) 405 (384–427) |
432 (402–465) 1037 (981–1097) |
2.15 (2.05–2.26) | 2.40 (2.27–2.53) |
| Fluvoxamine, 50 mg q.d. |
No Yes |
100 mg s.d. p.o. |
136 (125–148) 162 (150–176) |
329 (304–357) 379 (351–409) |
1.19 (1.18–1.21) | 1.15 (1.14–1.16) |
| Fluvoxamine, 50 mg q.d. |
No Yes |
100 mg q.d. p.o. |
188 (176–202) 224 (210–239) |
432 (402–465) 500 (466–535) |
1.15 (1.14–1.17) | 1.13 (1.12–1.14) |
| Rifampicin, 600 mg q.d. |
No Yes |
100 mg s.d. p.o. |
143 (131–155) 18.9 (16.5–21.8) |
341 (316–368) 38.7 (33.7–44.6) |
0.13 (0.12–0.15) | 0.11 (0.10–0.13) |
| Rifampicin, 600 mg q.d. |
No Yes |
100 mg q.d. p.o. |
198 (185–212) 25.4 (22.0–29.2) |
451 (421–482) 50.1 (43.5–57.8) |
0.13 (0.11–0.14) | 0.11 (0.10–0.13) |
| Rifampicin, 600 mg q.d. |
No Yes |
100 mg s.d. i.v. |
1103 (1070–1137) 850 (830–870) |
1358 (1315–1402) 976 (952–1000) |
0.77 (0.76–0.78) | 0.72 (0.71–0.73) |
| Efavirenz, 600 mg q.d. |
No Yes |
100 mg s.d. p.o. |
136 (125–148) 53.6 (48.1–59.8) |
329 (304–356) 120 (107–133) |
0.39 (0.37–0.42) | 0.36 (0.34–0.39) |
| Efavirenz, 600 mg q.d. |
No Yes |
100 mg q.d. p.o. |
189 (176–202) 74.5 (67.3–82.6) |
433 (402–466) 156 (140–174) |
0.40 (0.37–0.43) | 0.36 (0.33–0.39) |
Remibrutinib pharmacokinetics and DDI effects predicted by PBPK modeling. Pharmacokinetic data are presented as geometric means with 90% CI range in parentheses, AUC reported as AUCinf for single dose and AUCtau for multiple dose remibrutinib.
Abbreviations: AUC, area under the blood concentration‐time; CI, confidence interval; Cmax, maximum (peak) blood drug concentration; Cmax ratio, maximum (peak) blood drug concentration ratio; DDI, drug‐drug interaction; s.d, single‐dose; TMDD, target‐mediated drug disposition.