BTKi pharmacotherapy: Expert overview

Expert overview from hematologist Alessandra Tedeschi and pharmacologist Federico Pea

Introduction

Bruton's tyrosine kinase (BTK) inhibitors have proved to be a valuable treatment option for several B-cell malignancies, transforming outcomes for many patients.

In this short overview, hematologist Alessandra Tedeschi and pharmacologist Federico Pea outline the key pharmacotherapy considerations in the use of the BTK inhibitors ibrutinib, zanubrutinib, and acalabrutinib. Potential drug–drug interactions (DDIs) with BTK inhibitors and commonly prescribed medication are described, along with some background on mechanisms of DDIs.

Alessandra Tedeschi

Alessandra Tedeschi

Federico Pea

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 pharmacology8–14

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 management9,11,12
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 inhibitors9,11,12,19,20

DDI workstream diagram

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.
Alpha blockers Analgesics Angiotensin-II receptor blockers Antibiotics Anticholinergics Anticonvulsants Antidepressants Antidiabetics Antihistamines Anti-emetics Antifungals Antiplatelet therapies Antipsychotics Antithrombotics Beta blockers Calcium channel blockers Cardiac glycosides Diuretics Glucocorticoids Hypnotics Muscle relaxants Non-steroidal anti-inflammatory drugs (NSAIDs) Potassium channel blockers Proton pump inhibitors (PPIs) Sedatives Statins Urology
Tamsulosin, Terazosin Acetaminophen, Buprenorphine, Celecoxib, Codeine, Fentanyl, Hydrocodone, Hydromorphone, Meperidine, Methadone, Oxycodone, Piroxicam, Tramadol Irbesartan, Losartan, Valsartan Clarithromycin Clindamycin Rifampin Sulfamethoxazole Benztropine Carbamazepine Ethosuximide Phenytoin Valproic acid Amitriptyline Bupropion Citalopram Duloxetine Escitalopram Fluoxetine Mirtazapine Paroxetine Sertraline Trazodone Venlafaxine Glipizide, Metformin, Pioglitazone, Rosiglitazone Chlorpheniramine, Diphenhydramine, Hydroxyzine, Loratadine Metoclopramide Fluconazole Isavuconazonium Itraconazole Voriconazole Clopidogrel, Prasugrel, Ticagrelor Aripiprazole, Haloperidol, Olanzapine, Risperidone, Quetiapine, Ziprasidone Apixaban, Clopidogrel, Dabigatran, Rivaroxaban, Warfarin Carvedilol, Metoprolol, Propranolol, Sotalol Diltiazem Felodipine Verapamil Digoxin Triamterene Fluticasone Diazepam, Midazolam Carisoprodol, Cyclobenzaprine, Tizanidine Aspirin, Diclofenac, Etodolac, Ibuprofen, Indomethacin, Meloxicam, Naproxen, Piroxicam Amiodarone Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole Alprazolam, Diazepam, Eszopiclone, Zolpidem Atorvastatin, Lovastatin, Rosuvastatin, Simvastatin Sildenafil, Tadalafil
Ibrutinib Clarithromycin is a strong CYP3A4 inhibitorAvoid concomitant use Rifampin is a strong CYP3A4 inducerAvoid concomitant use Carbamazepine is a strong CYP3A4 inducerAvoid concomitant use Phenytoin is a strong CYP3A4 inducerAvoid concomitant use Citalopram may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Duloxetine may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Escitalopram may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Fluoxetine may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Paroxetine may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Sertraline may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Venlafaxine may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Fluconazole is a strong CYP3A4 inhibitorAvoid concomitant use Isavuconazonium is a strong CYP3A4 inhibitorAvoid concomitant use Itraconazole is a strong CYP3A4 inhibitorAvoid concomitant use Voriconazole is a strong CYP3A4 inhibitorAvoid concomitant use Clopidogrel, prasugrel, and ticagrelor may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Antithrombotics may increase the risk of bleeding Warfarin or other vitamin K antagonists should not be administered concomitantly with ibrutinib. Monitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Diltiazem is a moderate CYP3A4 inhibitorModify ibrutinib dose to 280 mg once daily Verapamil is a moderate CYP3A4 inhibitorModify ibrutinib dose to 280 mg once daily Digoxin is a P-gp substrateDigoxin should be taken at least 6 hours before or after ibrutinib. NSAIDs may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Amiodarone is a moderate CYP3A4 inhibitorModify ibrutinib dose to 280 mg once daily
Zanubrutinib Clarithromycin is a strong CYP3A4 inhibitorModify zanubrutinib dose to 80 mg once daily Rifampin is a strong CYP3A4 inducerAvoid concomitant use Carbamazepine is a strong CYP3A4 inducerAvoid concomitant use Phenytoin is a strong CYP3A4 inducerAvoid concomitant use Citalopram may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding and monitor complete blood counts. Duloxetine may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding and monitor complete blood counts. Escitalopram may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding and monitor complete blood counts. Fluoxetine may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding and monitor complete blood counts. Paroxetine may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding and monitor complete blood counts. Sertraline may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding and monitor complete blood counts. Venlafaxine may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding and monitor complete blood counts. Fluconazole is a strong CYP3A4 inhibitorModify zanubrutinib dose to 80 mg once daily Itraconazole is a strong CYP3A4 inhibitorAvoid concomitant use Itraconazole is a strong CYP3A4 inhibitorModify zanubrutinib dose to 80 mg once daily Voriconazole is a strong CYP3A4 inhibitorModify zanubrutinib dose to 80 mg once daily Clopidogrel, prasugrel, and ticagrelor may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding and monitor complete blood counts. Antithrombotics may increase the risk of bleedingWarfarin or other vitamin K antagonists should not be administered concomitantly with zanubrutinib. Monitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding and monitor complete blood counts. Diltiazem is a moderate CYP3A4 inhibitorModify zanubrutinib dose to 80 mg once daily Verapamil is a moderate CYP3A4 inhibitorModify zanubrutinib dose to 80 mg once daily Digoxin is a P-gp substrateZanubrutinib may increase the concentration of digoxin. NSAIDs may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding and monitor complete blood counts. Amiodarone is a moderate CYP3A4 inhibitorModify zanubrutinib dose to 80 mg once daily
Acalabrutinib Clarithromycin is a strong CYP3A4 inhibitorAvoid concomitant use Rifampin is a strong CYP3A4 inducerAvoid concomitant use Carbamazepine is a strong CYP3A4 inducerAvoid concomitant use Phenytoin is a strong CYP3A4 inducerAvoid concomitant use Citalopram may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Duloxetine may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Escitalopram may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Fluoxetine may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Paroxetine may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Sertraline may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Venlafaxine may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Fluconazole is a strong CYP3A4 inhibitorAvoid concomitant use. Itraconazole is a strong CYP3A4 inhibitorAvoid concomitant use Itraconazole is a strong CYP3A4 inhibitorAvoid concomitant use. Voriconazole is a strong CYP3A4 inhibitorAvoid concomitant use. Clopidogrel, prasugrel, and ticagrelor may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Antithrombotics may increase the risk of bleedingWarfarin or other vitamin K antagonists should not be administered concomitantly with acalabrutinib. Monitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Diltiazem is a moderate CYP3A4 inhibitorNo dose adjustment. Monitor patients closely for adverse reactions. Verapamil is a moderate CYP3A4 inhibitorNo dose adjustment. Monitor patients closely for adverse reactions. NSAIDs may increase the risk of bleedingMonitor patients receiving concomitant medications associated with a bleeding risk for signs and symptoms of bleeding. Amiodarone is a moderate CYP3A4 inhibitorNo dose adjustment. Monitor patients closely for adverse reactions. PPIs may interfere with acalabrutinib when administered as capsulesAvoid concomitant use with acalabrutinib 100 mg hard capsules; PPIs may be taken without dose adjustments with acalabrutinib 100 mg tablets.
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
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