Table 2.
General properties of approved BTK inhibitors.
| Property | Acalabrutinib (16, 19) | Ibrutinib (8, 16) | Zanubrutinib (42, 43) |
|---|---|---|---|
| Formulation | * Capsules: 100 mg | * Capsules: 70 and 140 mg | * Capsules: 80 mg |
| * Tablets: 140, 280, 420, and 560 mg | |||
| Dosing | * 100 mg every 12h | * MCL and MZL: 560 mg once daily | * 160 mg twice daily or 320 mg once daily |
| * CLL/SLL, WM: 420 mg once daily | |||
| Pharmacodynamics | * Median steady state BTK occupancy of ≥95% in peripheral blood; maintained over 12h with 100 mg dose | * >90% BTK active site occupancy in PBMCs up to 24h after ≥2.5 mg/kg/day | * Median steady state BTK occupancy of 100% in PBMCs; maintained over 24h with 320 mg daily dose |
| Pharmacokinetics | * Half-life: 1h | * Half-life: 4–6h | * Half-life: 2–4h |
| * Median Tmax: 0.9h | * Median Tmax: 1–2h | * Median Tmax: 2h | |
| * Main route of elimination: metabolism (mainly by CYP3A); primarily excreted via feces | * Main route of elimination: metabolism (mainly by CYP3A); primarily excreted via feces | * Main route of elimination: metabolism (mainly by CYP3A); primarily excreted via feces | |
| * No effect of mild or moderate renal impairment on PK (not evaluated in patients with severe renal impairment) | * Renal impairment effects PK | * No effect of mild or moderate renal impairment on PK (not evaluated in patients with severe renal impairment) | |
| Drug interactions | * CYP3A inhibitors: dose modification may be required | * CYP3A inhibitors: dose modification required | * CYP3A inhibitors: modify dose with moderate or strong CYP3A inhibitors |
| * CYP3A inducers: avoid co-administration with strong CYPA3 inducers | * CYP3A inducers: avoid co-administration with strong CYPA3 inducers | * CYP3A inducers: avoid co-administration with moderate or strong CYPA3 inducers | |
| * Gastric acid reducing agents: avoid administration with PPIs; stagger dosing with H2-receptor antagonists and antacids | |||
| Off-target effects (pathway level) | * Minimal | * EGFR family kinases | * Weak ITK |
| * Src family kinases | |||
| * Tec family kinases | |||
| Most common adverse reactions (≥30%) in patients with B-cell malignancies a | * Anemia | * Thrombocytopenia | * Neutrophil count decreased |
| * Neutropenia | * Diarrhea | * Platelet count decreased | |
| * Upper respiratory tract infection | * Fatigue | * Upper respiratory tract infection | |
| * Thrombocytopenia | * Musculoskeletal pain | * White blood cell count decreased | |
| * Headache | * Neutropenia | ||
| * Diarrhea | * Rash | ||
| * Musculoskeletal pain | * Anemia | ||
| * Bruising | |||
| Clinically significant adverse reactions a | * Major hemorrhage b (3%) | * Major hemorrhage b (4%) | * Grade ≥3 bleeding events (2%) |
| * Serious or grade ≥3 infections (19%) | * Grade ≥3 infections (21%) | * Grade ≥3 infections (23%) | |
| * Grade 3 or 4 neutropenia (23%) | * Grade 3 or 4 neutropenia (23%) | * Grade 3 or 4 neutropenia (27%) | |
| * Grade 3 or 4 anemia (8%) | * Grade 3 or 4 thrombocytopenia (8%) | * Grade 3 or 4 thrombocytopenia (10%) | |
| * Grade 3 or 4 thrombocytopenia (7%) | * Grade 3 or 4 anemia (3%) | * Grade 3 or 4 anemia (8%) | |
| * Grade 3 or 4 lymphopenia (7%) | * Cardiac arrhythmias (grade ≥3 ventricular tachyarrhythmias, 0.2%; grade ≥3 atrial fibrillation and atrial flutter, 4%) | * Second primary malignancies (9%; skin cancer [6%]) | |
| * Second primary malignancies (12%; skin cancer [6%]) | * Hypertension (all grades, 19%; grade ≥3, 8%) | * Cardiac arrhythmias (all grades, 2%; grade ≥3, 0.6%) | |
| * Cardiac arrhythmias (all grades, 4.1%; grade 3, 1.1%) | * Second primary malignancies (other malignancies, 10% [including non-skin carcinomas, 4%]; non-melanoma skin cancer, 6%) |
BTK, Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; CYP3A, cytochrome P450 family 3 subfamily A; EGFR, epidermal growth factor receptor; ITK, interleukin-2-inducible T-cell kinase; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; PBMC, peripheral blood mononuclear cells; PK, pharmacokinetics; SLL, small lymphocytic leukemia; WM, Waldenstrom’s macroglobulinemia.
a
Adverse reaction data are reported for patients receiving monotherapy and are reported as percentages of patients who reported the adverse reaction.
b
Serious or grade ≥3 bleeding or any central nervous system bleeding.