Table 1.

Description and pharmacological properties of approved BTK inhibitors and those in later-stage clinical development

Parameter	Ibrutinib [3–5]	Acalabrutinib [6–8]	Zanubrutinib [9–11]	Tirabrutinib [12–17]	Orelabrutinib [18, 19]	Pirtobrutinib [20, 21]	Nemtabrutinib [22, 23]
Mode of binding	Covalent, irreversible	Covalent, irreversible	Covalent, irreversible	Covalent, irreversible	Covalent, irreversible	Non-covalent, reversible	Non-covalent, reversible
BTK binding site	Cys-481	Cys-481	Cys-481	Cys-481	Cys-481	ATP-binding sitea	ATP-binding sitea
Selectivity	Moderate	High	High	High	High	High	Moderate
IC50
BTK	0.5 nM	3.0–5.1 nM	0.3 nM	6.8 nM	1.6 nM	3.15 nM	0.85 nM
BMX	0.8 nM	46 nM		6 nM			5.2 nM
EGFR	5.3 nM	> 1000 nM	21 nM	> 1000 nM
HER2	9.4 nM	> 1000 nM	661 nM	> 1000 nM
HER4		16 nM		770 nM
ITK	4.9 nM	> 1000 nM	50 nM	> 1000 nM			>10,000 nM
JAK3	32 nM	> 1000 nM	> 1000 nM	> 1000 nM
TEC	10 nM	126 nM	44 nM	77 nM			5.8 nM
Absolute bioavailability	< 10%	25%	45–50%b	89%b	~20–80%	70–74%b
Half-life	4–13 h	1–2 h	2–4 h	4–7 h	1.5–4 h	~20 h	20–30 h
Target occupancy in PBMCs	> 90%	97–99%	> 95%	> 90%	> 99%	>96%
Metabolism	Predominantly via CYP3A	Predominantly via CYP3A	Predominantly via CYP3A	Predominantly via CYP3A	Predominantly via CYP3A
Excretion	Faeces, 80%; urine, < 10%	Faeces, 84%; urine, 12%	Faeces, 87%; urine, 8%	Faeces, 52%; urine, 42%	Faeces, 49%; urine, 34%

BMX bone marrow kinase on chromosome X, BTK Bruton tyrosine kinase, EGFR epidermal growth factor receptor, HER2 human EGFR 2, HER4 human EGFR 4, ITK interleukin-2-inducible T-cell kinase, JAK3 Janus kinase 3, TEC transient erythroblastopenia of childhood kinase, PBMCs peripheral blood mononuclear cells

^aWithout requiring binding at Cys-481

^bBased on animal data