BTKi pharmacotherapy: Expert overview

Introduction

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), and no known interaction. Interactions may increase (↑) or decrease (↓) a patient's exposure to a BTK inhibitor.

References

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