Clinical pharmacology and PK/PD translation of the second-generation Bruton’s tyrosine kinase inhibitor, zanubrutinib

Figures & data

Table 1. Approved dose regimens and key clinical pharmacology properties of zanubrutinib relative to those of ibrutinib and acalabrutinib

	Zanubrutinib	Ibrutinib	Acalabrutinib
Approved indications	MCL, WM*	MCL, CLL, and WM. MZL chronic graft versus host disease (cGVHD)	MCL, CLL
FDA approved dose	160 mg BID or 320 mg QD	420 or 560 mg QD	100 mg BID
IC50 against BTK (nM) [24]	0.5	1.5	5.1
Potency of major active metabolite against BTK	NA	~15-fold less potent compared to the parent molecule [15]	~2-fold less potent compared to the parent molecule [24]
Half-life (hr)	~2 to 4	~4 to 6	~0.6 to 2.8
Plasma protein binding (%)	~94%	97.3% – 97.7% [15]	97.4% – 97.5% [57]
AUC0-24hr (CV%) ng·hr/mL	160 mg BID: 2295 (37%) 320 mg QD: 2180 (41%)	420 mg QD: 707–1159 (50%-72%) 560 mg QD: 865–978 (69%-82%)	100 mg BID: 1843- (38%) −1850 (72%) [29]
fu. AUC0-24hr (nM·hr)	160 mg BID: 278 320 mg QD: 267	420 mg QD: 37–60 560 mg QD: 46–51	100 mg BID: 103
Plasma exposure of major active metabolite	NA	1- to 2.8-fold higher than parent AUC [15]	2- to 3-fold higher than parent AUC [57]
Median BTK occupancy in PBMC at trough	320 mg QD:100% 160 mg BID: 100%	420 mg to 820 mg QD: >90% [30,33]	100 mg BID: ≥95% [32]
Median BTK occupancy in lymph node at trough	320 mg QD: 94% 160 mg BID: 100%	420 mg QD: >90% [16]	200 mg QD: 90% 100 mg BID: 95.8% [34]
Pgp and brain penetration	Weak P-gp substrate Brain penetration data in patients available	Not a P-gp substrate Brain penetration data in patients available	P-gp substrate Likely limited brain penetration
Major enzyme involved	CYP3A	CYP3A	CYP3A

Note: If not noted, data were taken from respective US Prescription for zanubrutinib [9], ibrutinib [17], and acalabrutinib [28].

* Zanubrutinib is approved in WM (based on Product Monograph in Health Canada) AUC₂₄ area under the plasma concentration-time curve from time zero to 24 h, BID twice daily, BTK Bruton's tyrosine kinase, CLL chronic lymphocytic leukemia, fu fraction of unbound drug in plasma, IC₅₀ concentration for 50% inhibition, MCL mantle cell lymphoma, PBMC peripheral blood mononuclear cell, PD pharmacodynamic, PK pharmacokinetic, QD once daily, WM Waldenström macroglobulinemia, NA not applicable.

Figure 1. Chemical structure of zanubrutinib

Table 2. Kinase selectivity of zanubrutinib, ibrutinib, and acalabrutinib

Kinase^a	Zanubrutinib selectivity	Ibrutinib selectivity^b	Acalabrutinib selectivity
			Parent compound^c	Metabolite ACP-5862^d
EGFR	42	3.5	196	NA
ITK	100	3.3	196	NA
TEC	88	6.7	25	69
HER2	176	4.3	196	NA
HER4	13.8	2.3	3.1	69
BMX	2.8	0.5	9.0	3.0
TXK	4.4	1.3	72	NA
BLK	5.0	0.1	196	NA
JAK3	2754	21	196	NA

Bold text represents selectivity of >10-fold.^aSelectivity of parent compound was calculated based on IC₅₀ of each kinase relative to BTK IC₅₀ of zanubrutinib (0.5 nM), ibrutinib (1.5 nM), and acalabrutinib (5.1 nM) based on the publication of Kaptein et al [24], in which head-to-head comparison of BTK potency and activity on other kinases by zanubrutinib, ibrutinib, and acalabrutinib were reported.

# # # ^bThe selectivity data for ibrutinib major active metabolite (PCI-45227) are not available, thus not summarized here. It was noted that PCI-45227 is more selective in comparison to ibrutinib [15].

# # # ^cWhen IC₅₀ values of kinases could not be determined (estimated to be >1000 nM), the selectivity of these kinases was calculated by using IC₅₀ value of 1000 nM, so the actual selectivity could be higher than 196.

# # ^dSelectivity of ACP-5862 for TEC, HER4, and BMX was calculated based on IC₅₀ of each kinase relative to BTK IC₅₀ of ACP-5862, as reported in the FDA Summary Basis of Approval [39]. As IC₅₀ values were only available for 3 kinases (TEC, HER4, and BMX), the activity of ACP-5862 on other kinase activities and its contributions to potential off-target effects remain unknown.

# # NA not available.

Figure 2. Plasma concentration-time profile of zanubrutinib after single dosing. Error bars indicate standard deviation [27]

Figure 3. Free drug concentration time profiles relative to IC₅₀ of approved BTK inhibitors

BTK potencies of zanubrutinib, ibrutinib, and acalabrutinib (IC₅₀) were based on biochemical assays from the publication of Kaptein et al.[24] PK and plasma protein-binding data were obtained from published work [15,29,30,49,57,67]. The concentration time profiles for ibrutinib major active metabolite (PCI-45227) at 560 mg are not available, thus not summarized here. It was noted that PCI-45227 is ~15-fold less potent compared to the parent molecule [15].

Figure 4. (A) Zanubrutinib BTK occupancy in peripheral blood mononuclear cells by dose regimen. (B) Zanubrutinib BTK occupancy in lymph nodes by dose regimen. Median values are shown as lines through the individual symbols. BID twice a day, BTK Bruton’s tyrosine kinase, N number of patients, QD once a day, W1D1 Week 1 Day 1, W1D3, Week 1 Day 3, W2D1 Week 2 Day 1 [11]. Predose samples were collected 24 hours after dosing for the QD dose or 12 hr after dosing for the BID dose. Samples were collected 4 hours after dose for ‘W1D1 4 hours’ samples. Republished in part with permission of Elsevier Science & Technology Journals, from Tam CSL, Trotman J, Opat S, et al. Phase 1 study of selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019;134(11):851–859; permission conveyed through Copyright Clearance Center, Inc

Table 3. Comparison of extrinsic and intrinsic factors impacting zanubrutinib, ibrutinib, and acalabrutinib

	Zanubrutinib	Ibrutinib	Acalabrutinib
Food Effect
Clinical Data (Low or high-fat meal)	No clinically meaningful impact on PK	Cmax: 2- to 4-fold increase AUC: 2-fold increase	No clinically meaningful impact on PK
Label recommendation	Dose with or without food	Dose with or without food	Dose with or without food
Use with CYP3A inhibitors
Clinical Data	Itraconazole increased AUC 3.8-fold (Fasted, HV)	Ketoconazole increased AUC 24-fold (Fasted, HV) Voriconazole (strong CYP3A inhibitor) increased steady state Cmax of ibrutinib by 6.7-fold and AUC by 5.7-fold (non-fasted, patients).	Itraconazole increased AUC 5.1-fold (Fasted, HV)
Label recommendation	Strong CYP3A inhibitor: Dose reduction to 80 mg QD Moderate inhibitors: dose reduction to 80 mg BID	Avoid strong CYP3A inhibitors except for posaconazole and voriconazole. If these inhibitors will be used short-term (such as anti-infectives for seven days or less), interrupt ibrutinib Moderate CYP3A inhibitor: dose reduction to 280 mg once daily	Avoid concomitant use with strong CYP3A inhibitors. If these inhibitors will be used short-term (such as anti-infectives for up to seven days), interrupt acalabrutinib. Moderate CYP3A inhibitor: dose reduction to 100 mg QD
Use with CYP3A inducers
Clinical Data: With potent CYP 3A Inducer rifampin	Reduced AUC by 13.5-fold	Reduced AUC by >10-fold	Reduced AUC by 4.3-fold
Label recommendation	Avoid moderate and strong CYP3A inducers	Avoid moderate and strong CYP3A inducers	Avoid strong CYP3A inducers; 200 mg BID if no alternative
Use with ARA including PPI
Clinical DDI Data:	No clinically meaningful impact on PK	No clinically meaningful impact on PK	1 g calcium carbonate decreased AUC 53%; omeprazole decreased AUC by 43%
Label recommendation	No restriction	No restriction	Avoid PPIs, separate antacid dosing by at least 2 hr, take drug 2 hr before H2 blockers
Hepatic impairment
Clinical data	AUC relative to subjects with normal liver function: Mild: 111% Moderate: 121% Severe: 160%	AUC relative to subjects with normal liver function: Mild: 270% Moderate: 820% Severe: 980%	AUC relative to subjects with normal liver function: Mild: 190% Moderate: 150% Severe: 530%
Label recommendation	Severe: 80 mg BID Mild/Moderate: No dosage modification	Severe: Avoid Moderate: Dose reduction to 70 mg QD Mild: Dose reduction 140 mg QD	Severe: Avoid Mild/Moderate: No dosage modification
Renal impairment
Clinical data	Mild and moderate renal impairment ([CLcr] ≥ 30 mL/min) had no influence on the exposure	Mild and moderate renal impairment ([CLcr] > 25 mL/min) had no influence on the exposure	No clinically relevant PK difference in patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m^2*)
Label Recommendation	Mild/moderate renal impairment (CLcr ≥ 30 mL/min): No dose modification	NA	NA

Note: If not noted, data were taken from respective US Prescription for Zanubrutinib [9], Ibrutinib [17], and Acalabrutinib [28].

*eGFR as estimated by MDRD (modification of diet in renal disease equation).

ARA acid reducing agent, AUC area under the plasma concentration–time curve, BID twice daily, CLcr creatinine clearance as estimated by Cockcroft-Gault equation, C_max maximum plasma concentration, CYP cytochrome P450, DDI drug–drug interaction, eGFR estimated glomerular filtration rate, NA not available, PPI proton pump inhibitor.

Table 4. Comparison of response rates between two dose regimens of zanubrutinib in patients with B-cell malignancies in study BGB-3111-AU-003

	160 mg BID	320 mg QD
R/R MCL	N = 14	N = 18
CR, n (%)	4 (28.6)	4 (22.2)
ORR^a, n (%)	12 (85.7)	15 (83.3)
R/R and treatment naïve CLL	N = 81	N = 40
CR, n (%)	11 (13.6)	9 (22.5)
ORR^b, n (%)	76 (93.8)	40 (100.0)
R/R and treatment naïve WM	N = 47	N = 22
VGPR + CR rate, n (%)	23 (48.9)	7 (31.8)
ORR^c, n (%)	46 (97.9)	20 (90.9)

Note: Clinical data summarized were from the work of Tam et al, 2019 [82] for MCL, Tam et al, 2019 [11] for CLL, and Trotman et al, 2020 [83] for WM.

Confidence intervals for all disease indications were overlapping between the two dose regimens.

^aORR in patients with R/R MCL: the proportion of patients that have an assessment of PR and CR.

^bORR in patient with R/R and treatment naïve CLL: the proportion of patients that have an assessment of PR-L or higher (PR, VGPR, and CR).

^cORR in patient with R/R and treatment naïve WM: the proportion of patients that have an assessment of MR or higher (PR, VGPR, and CR).

BID twice daily, CLL chronic lymphocytic lymphoma, CR complete response, MCL mantle cell lymphoma, MR minimal response, ORR objective response rate, PR partial response, PR-L partial response with lymphocytosis, QD once daily, R/R relapsed/refractory, VGPR very good partial response, WM Waldenström macroglobulinemia.

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