Table 4.
Simulated Cmax and AUC0‐24 h ratios of zanubrutinib at steady state in the presence and absence of CYP modulators.
| Inhibitor/inducer | Dose (mg) | Treatment (days) | No. of subjects (trials) | Dose regimen | Cmax ratio | AUC0‐24 h ratio |
|---|---|---|---|---|---|---|
| Strong CYP3A inhibitors | ||||||
| Ritonavir | 100 | 14 | 100 (10) | b.i.d. | 6.68 | 8.32 |
| Itraconazole | 200 | 14 | 100 (10) | q.d. | 3.95 | 2.97 |
| Clarithromycin | 250 | 14 | 100 (10) | b.i.d. | 2.75 | 2.83 |
| Moderate CYP3A inhibitors | ||||||
| Erythromycin | 500 | 14 | 100 (10) | q.6.h. | 3.84 | 4.17 |
| Fluconazole | 200 | 14 | 100 (10) | q.d. | 2.79 | 2.77 |
| Fluconazole | 400 | 14 | 100 (10) | q.d. | 3.70 | 3.84 |
| Diltiazem | 60 | 14 | 100 (10) | q.8.h. | 2.51 | 2.57 |
| Ciprofloxacin | 500 | 14 | 100 (10) | q.8.h. | 1.00 | 1.00 |
| Mild CYP3A inhibitors | ||||||
| Fluvoxamine | 50 | 14 | 100 (10) | q.d. | 1.12 | 1.09 |
| Cyclosporine | 200 | 14 | 100 (10) | q.d. | 1.19 | 1.11 |
| Cimetidine | 400 | 14 | 100 (10) | b.i.d. | 1.00 | 1.00 |
| Strong CYP3A inducers | ||||||
| Rifampicin | 600 | 14 | 100 (10) | q.d. | 0.07 | 0.07 |
| Carbamazepine | 400 | 14 | 100 (10) | b.i.d. | 0.39 | 0.42 |
| Moderate CYP3A inducer | ||||||
| Efavirenz | 600 | 14 | 100 (10) | q.d. | 0.42 | 0.40 |
Simulation conditions: 10 virtual trials, each trial included 10 subjects (aged 20–50 years and 50% female). Each subject received an inhibitor or inducer for 14 days; zanubrutinib 160 mg b.i.d. was administered from Day 7 to Day 14. Geometric mean ratios (with/without perpetrator) for AUC and Cmax are provided ([substrate +interaction]/substrate). For an inducer, %decrease = (1‐ ratio)*100% is also shown.
Abbreviations: AUC, area under the plasma concentration–time curve; AUC0‐24 h, area under the plasma concentration–time curve from time 0 to 24 hours; b.i.d., twice daily; Cmax, maximum plasma concentration; q.6.h., every 6 hours; q.8.h., every 8 hours; q.d., once daily.