BTKi pharmacotherapy:
Expert overview

Expert overview from hematologist Alessandra Tedeschi and pharmacologist Federico Pea

BTK inhibition

Ibrutinib was the first-in-class BTK inhibitor, initially receiving approval for MCL in 2013.¹ It offers deep and durable responses with an acceptable toxicity profile, but patients may experience side effects attributed to significant off-target activity.² Cardiovascular adverse drug reactions are a notable challenge, with substantial real-world incidence of atrial fibrillation and hypertension among patients treated with ibrutinib.^2-4

The next-generation BTK inhibitors zanubrutinib and acalabrutinib have greater selectivity for BTK compared with ibrutinib and have consistently demonstrated some notable advantages in terms of safety in head-to-head trials versus ibrutinib.^5-7 Notably, zanubrutinib and acalabrutinib have favorable cardiac safety profiles compared with ibrutinib.^5-7

Efficacy outcomes have usually been similar between BTK inhibitors in head-to-head trials. However, in the ALPINE study in relapsed/refractory (R/R) CLL, zanubrutinib demonstrated a better overall response rate (83.5% vs. 74.2%) and 24-month progression-free survival (78.4% vs. 65.9%; hazard ratio: 0.65; P=0.002) versus ibrutinib.⁷

These three covalent BTK inhibitors are currently approved as monotherapies by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for the treatment of four B-cell malignancies (see Table 1).^8–13

Table 1. BTK inhibitor approvals in B-cell malignancies and pharmacology^8–14

	Ibrutinib	Zanubrutinib	Acalabrutinib
Approved indications in Europe (EMA)	CLL*, MCL, WM^†	CLL, MZL, WM	CLL^‡
Approved indications in the USA (FDA)	CLL*, WM^†	CLL, MCL, MZL, WM	CLL^‡, MCL
Pharmaceutical forms in Europe (EMA)	Hard capsule: 140 mg Tablets: 140 mg, 280 mg, 420 mg, and 560 mg	Hard capsule: 80 mg	Hard capsule: 100 mg Tablet: 100 mg
Pharmaceutical forms in the USA (FDA)	Capsules: 70 mg and 140 mg Tablets: 140 mg, 280 mg, and 420 mg Oral suspension: 70 mg/mL	Hard capsule: 80 mg	Hard capsule: 100 mg Tablet: 100 mg
Approved dose	420 mg QD for CLL and WM 560 mg QD for MCL	160 mg BID or 320 mg QD	100 mg BID
IC₅₀ against BTK, nM	1.5	0.5	5.1
Potency of major active metabolite against BTK	~15-fold less potent compared with the parent molecule	N/A	~2-fold less potent compared with the parent molecule
Half-life, hours	~4 to 6	~2 to 4	~0.6 to 2.8
Plasma protein binding, %	97.3–97.7	~94	97.4–97.5
AUC₀_–_24h (CV%), ng·h/mL	420 mg QD: 707–1,159 (50%–72%) 560 mg QD: 865–978 (69%–82%)	160 mg BID: 2,295 (37%) 320 mg QD: 2,180 (41%)	100 mg BID: 1,843–1,850 (38%–72%)
fu. AUC₀_–_24h, nM·h	420 mg QD: 37–60 560 mg QD: 46–51	160 mg BID: 278 320 mg QD: 267	100 mg BID: 103
Plasma exposure of major active metabolite	1- to 2.8-fold higher than parent AUC	N/A	2- to 3-fold higher than parent AUC
Median BTK occupancy in PBMC at trough	420 mg to 820 mg QD: >90%	160 mg BID: 100% 320 mg QD:100%	100 mg BID: ≥95%
Median BTK occupancy in lymph node at trough	420 mg QD: >90%	160 mg BID: 100% 320 mg QD: 94%	100 mg BID: 95.8% 200 mg QD: 90%
P-gp and brain penetration	Not a P-gp substrate. Brain penetration data in patients available.	Weak P-gp substrate. Brain penetration data in patients available.	P-gp substrate. Likely limited brain penetration.

*Approved as monotherapy or with obinutuzumab, rituximab, or venetoclax for previously untreated CLL and as monotherapy or with bendamustine and rituximab for previously treated CLL. †Approved as monotherapy or with rituximab for previously treated patients and untreated patients unsuitable for chemoimmunotherapy. ‡Approved as monotherapy or with obinutuzumab. AUC, area under the curve; BID, twice a day; fu., fraction of unbound drug in plasma; IC50, half maximal inhibitory concentration; N/A, not applicable; PBMC, peripheral blood mononuclear cell; QD, once a day.

Tolerability with BTK inhibitors

Side effects associated with BTK inhibitors are usually manageable, but withdrawal or discontinuation of the agents may be required in some circumstances (see Table 2).2,5–7

Table 2. BTK inhibitor side effect management^9,11,12

	Dose adjustments or discontinuation
Ibrutinib	Ibrutinib should be withheld on the first, second, and third occurrence and discontinued after the fourth occurrence of Grade 3 or 4 non-hematological toxicities; Grade 3 or 4 neutropenia with infection or fever; and Grade 4 hematological toxicities Ibrutinib should be withheld on the first and second occurrence, and discontinued after the third occurrence of Grade 2 cardiac failure Ibrutinib should be withheld on the first occurrence and discontinued after the second occurrence of Grade 3 cardiac arrhythmias Ibrutinib should be discontinued after the first occurrence of Grade 3 or 4 cardiac failure or Grade 4 cardiac arrhythmias
Zanubrutinib	Zanubrutinib should be withheld on the first, second, and third occurrence and discontinued after the fourth occurrence of Grade ≥3 non-hematological toxicities; Grade 3 febrile neutropenia; Grade 3 thrombocytopenia with significant bleeding; Grade 4 neutropenia (lasting >10 consecutive days); or Grade 4 thrombocytopenia (lasting >10 consecutive days)
Acalabrutinib	Acalabrutinib should be withheld on the first, second, and third occurrence and discontinued after the fourth occurrence of Grade 3 thrombocytopenia with bleeding; or Grade 4 thrombocytopenia or Grade 4 neutropenia lasting longer than 7 days; or Grade 3 or greater non-hematological toxicities

DDI overview

Monitoring and managing the risk of potential DDIs is an important component of treatment with any drug, including BTK inhibitor therapy. Most patients with CLL, WM, MCL, or MZL are ≥60 years old at diagnosis and likely to have comorbidities that require medication.15–18 Acute conditions (such as infections) that require treatment will also arise over time in this patient population.

DDIs occur when one drug alters the activity of another drug and result from pharmacokinetic and/or pharmacodynamic mechanisms, both of which are relevant to BTK inhibitors (see Figure 1).¹⁹

Figure 1. DDIs with BTK inhibitors^{9,11,12,19,20}

Table 3. Potential DDIs with ibrutinib, zanubrutinib, and acalabrutinib in patients with B-cell malignancies

Interaction strength:

X MAJOR
(highly clinically significant)
⚠ MODERATE
(moderately clinically significant)
NO KNOWN INTERACTION.
Interactions may increase (↑) or decrease (↓) a patient’s exposure to a BTK inhibitor.

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This table is for educational purposes only, not professional advice, and is not intended for a comparison of the three agents. The interaction strength of potential DDIs is based on the evaluation of information within the prescribing information or summary of product characteristics of each BTK inhibitor and other published studies.8–13,21,22 No known interaction was assumed with a particular drug if no interaction data could be found, but this does not mean no interaction can occur in patients.

Key takeaway messages

BTK inhibition has transformed outcomes for many patients with B-cell malignancies, but there are specific pharmacotherapy challenges associated with agents that are usually administered as continuous daily therapy, often over many years
Covalent BTK inhibitors have the same mode of action, but next-generation agents have favorable safety profiles versus ibrutinib, with acalabrutinib (ELEVATE-RR) and zanubrutinib (ALPINE and ASPEN) leading to fewer treatment discontinuations and cardiovascular adverse events compared to ibrutinib
Zanubrutinib has demonstrated superior efficacy versus ibrutinib in R/R CLL, while acalabrutinib showed non-inferior efficacy compared to ibrutinib
Side effects associated with BTK inhibitors are usually manageable, but dose reductions or discontinuations are necessary in some circumstances
At initial treatment selection and in the long-term management of patients, physicians must be aware of the potential for DDIs with BTK inhibitors
Most of the clinically relevant DDIs with BTK inhibitors relate to concomitant usage with inhibitors or inducers of CYP3A4 and/or agents associated with a bleeding risk

Please refer to the current health authority-approved product information for definitive guidance on each medicine’s drug interactions and recommended management.8–13

References:

Drugs.com. Imbruvica FDA approval history. Available at: https://www.drugs.com/history/imbruvica.html. Accessed June 2023.
Buske C, Jurczak W, Salem J-E et al. Managing Waldenström’s macroglobulinemia with BTK inhibitors. Leukemia 2023; 37 (1): 35–46.
Baptiste F, Cautela J, Ancedy Y et al. High incidence of atrial fibrillation in patients treated with ibrutinib. Open Heart 2019; 6 (1): e001049.
Dickerson T, Wiczer T, Waller A et al. Hypertension and incident cardiovascular events following ibrutinib initiation. Blood 2019; 134 (22): 1919–1928.
Byrd JC, Hillmen P, Ghia P et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: Results of the first randomized phase III trial. J Clin Oncol 2021; 39 (31): 3441–3452.
Tam CS, Opat S, D’Sa S et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: The ASPEN study. Blood 2020; 136 (18): 2038–2050.
Brown JR, Eichhorst B, Hillmen P et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 2023; 388 (4): 319–332.
Pharmacyclics LLC. IMBRUVICA – US prescribing information. Pharmacyclics LLC; South San Francisco, CA, USA, May 2023.
AstraZeneca AB. Calquence 100 mg hard capsules – summary of product characteristics. AstraZeneca AB; Södertälje, Sweden, May 2023.
AstraZeneca Pharmaceuticals LP. CALQUENCE (acalabrutinib) tablets, for oral use – US prescribing information. AstraZeneca Pharmaceuticals LP; Wilmington, DE, USA, August 2022.
Janssen-Cilag International NV. IMBRUVICA 140 mg hard capsules – summary of product characteristics. Janssen-Cilag International NV; Beerse, Belgium, April 2023.
BeiGene Ireland Ltd. BRUKINSA 80 mg hard capsules – summary of product characteristics. BeiGene Ireland Ltd; Dublin, Ireland, March 2023.
BeiGene USA, Inc. BRUKINSA (zanubrutinib) capsules, for oral use – US prescribing information. BeiGene USA, Inc., San Mateo, CA, USA, April 2023.
Tam CS, Ou YC, Trotman J et al. Clinical pharmacology and PK/PD translation of the second-generation Bruton’s tyrosine kinase inhibitor, zanubrutinib. Expert Rev Clin Pharmacol 2021; 14 (11): 1329–1344.
Eichhorst B, Robak T, Montserrat E et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2021; 32 (1): 23–33.
Dreyling M, Campo E, Hermine O et al. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28 (Suppl 4): iv62–iv71.
Cheah CY, Zucca E, Rossi D et al. Marginal zone lymphoma: Present status and future perspectives. Haematologica 2022; 107 (1): 35–43.
Kastritis E, Leblond V, Dimopoulos MA et al. Waldenström’s macroglobulinaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018; 29 (Suppl 4): iv41–iv50.
Niu J, Straubinger RM and Mager DE. Pharmacodynamic drug–drug interactions. Clin Pharmacol Ther 2019; 105 (6): 1395–1406.
Fancher KM and Pappacena JJ. Drug interactions with Bruton’s tyrosine kinase inhibitors: Clinical implications and management. Cancer Chemother Pharmacol 2020; 86 (4): 507–515.
de Abajo FJ, García-Rodríguez LA. Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-inflammatory drugs and effect of acid-suppressing agents. Arch Gen Psychiatry 2008; 65 (7): 795–803.
Pilla Reddy V, Fretland AJ, Zhou D et al. Mechanistic physiology-based pharmacokinetic modeling to elucidate vincristine-induced peripheral neuropathy following treatment with novel kinase inhibitors. Cancer Chemother Pharmacol 2021; 88 (3): 451–464.

BTKi pharmacotherapy: Expert overview