Acalabrutinib

Identification

Summary

Acalabrutinib is a Bruton tyrosine kinase inhibitor used to treat mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma.

Brand Names
Calquence
Generic Name
Acalabrutinib
DrugBank Accession Number
DB11703
Background

To date, acalabrutinib has been used in trials studying the treatment of B-All, myelofibrosis, ovarian cancer, multiple myeloma, and Hodgkin lymphoma, among others.

As of October 31, 2017 the FDA approved Astra Zeneca's orally administered Calquence (acalabrutinib, capsules). This Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, and in adult patients with Mantle cell lymphoma (MCL) who have already received at least one prior therapy.6 In August 2022, the FDA approved a new tablet formulation of Calquence, enabling the co-administration of this drug with proton pump inhibitors (PPIs).7,8 Unlike Calquence capsules, the co-administration of Calquence tablets and PPIs does not have an effect in the pharmacokinetics of acalabrutinib.6,7

Also known as ACP-196, acalabrutinib is also considered a second generation BTK inhibitor because it was rationally designed to be more potent and selective than ibrutinib, theoretically expected to demonstrate fewer adverse effects owing to minimized bystander effects on targets other than BTK.

Nevertheless, acalabrutinib was approved under the FDA's accelerated approval pathway, which is based upon overall response rate and faciliates earlier approval of medicines that treat serious conditions or/and that fill an unmet medical need based on a surrogate endpoint. Continued approval for acalabrutinib's currently accepted indication may subsequently be contingent upon ongoing verification and description of clinical benefit in confimatory trials.

Furthermore, the FDA granted this medication Priority Review and Breakthrough Therapy designations. It also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. At this time, more than 35 clinical trials across 40 countries with more than 2500 patients are underway or have been completed with regards to further research into better understanding and expanding the therapeutic uses of acalabrutinib 5.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 465.517
Monoisotopic: 465.191323009
Chemical Formula
C26H23N7O2
Synonyms
  • Acalabrutinib
  • Acalabrutinibum
External IDs
  • ACP-196

Pharmacology

Indication

Acalabrutinib is currently indicated for the treatment of adult patients with Mantle Cell Lymphoma (MCL) who have received at least one prior therapy.6 It has also been recently approved for chronic lymphocytic leukemia and small lymphocytic lymphoma.6

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofChronic lymphocytic leukaemia (cll)••••••••••••
Treatment ofMantle cell lymphoma•••••••••••••••••• • ••••• ••••••• ••• •••••• •••• ••••••••
Treatment ofSmall lymphocytic lymphoma (sll)••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Acalabrutinib is a Bruton Tyrosine Kinase inhibitor that prevents the proliferation, trafficking, chemotaxis, and adhesion of B cells.6 It is taken every 12 hours and can cause other effects such as atrial fibrillation, other malignancies, cytopenia, hemorrhage, and infection.6

Mechanism of action

Mantle Cell Lymphoma (MCL) is a rare yet aggressive type of B-cell non-Hodgkin lymphoma (NHL) with poor prognosis 2,4. Subsequently, relapse is common in MCL patients and ultimately represents disease progression 4.

Lymphoma occurs when immune system lymphocytes grow and multiply uncontrollably. Such cancerous lymphocytes may travel to many parts of the body, including the lymph nodes, spleen, bone marrow, blood, and other organs where they can multiply and form a mass(es) called a tumor. One of the main kinds of lymphocytes that can develop into cancerous lymphomas are the body's own B-lymphocytes (B-cells) 4.

Bruton Tyrosine Kinase (BTK) is a signalling molecule of the B-cell antigen receptor and cytokine receptor pathways. Such BTK signaling causes the activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.6

Acalabrutinib is a small molecule inhibitor of BTK. Both acalabrutinib and its active metabolite, ACP-5862, act to form a covalent bond with a cysteine residue (Cys481) in the BTK active site, leading to inhibition of BTK enzymatic activity.2,4 As a result, acalabrutinib inhibits BTK-mediated activation of downstream signaling proteins CD86 and CD69, which ultimately inhibits malignant B-cell proliferation and survival4

Whereas ibrutinib is typically recognized as the first-in-class BTK inhibitor,2 acalabrutinib is considered a second generation BTK inhibitor primarily because it demonstrates highter selectivity and inhibition of the targeted activity of BTK while having a much greater IC50 or otherwise virtually no inhibition on the kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1.2

In effect, acalabrutinib was rationally designed to be more potent and selective than ibrutinib, all the while demonstrating fewer adverse effects - in theory - because of the drug's minimized off target effects.

TargetActionsOrganism
ATyrosine-protein kinase BTK
inhibitor
Humans
Absorption

The geometric mean absolute bioavailability of acalabrutinib is 25% with a median time to peak plasma concentrations (Tmax) of 0.75 hours.6

Volume of distribution

The mean steady-state volume of distribution is approximately 34 L.6

Protein binding

Reversible binding of acalabrutinib to human plasma protein is approximately 97.5%. The in vitro mean blood-to-plasma ratio is about 0.7.6 In vitro experiments at physiologic concentrations show that acalabrutinib can be 93.7% bound to human serum albumin and 41.1% bound to alpha-1-acid glycoprotein.3

Metabolism

Acalabrutinib is mainly metabolized by CYP3A enzymes. ACP-5862 is identified to be the major active metabolite in plasma with a geometric mean exposure (AUC) that is about 2-3 times greater than the exposure of acalabrutinib. ACP-5862 is about 50% less potent than acalabrutinib in regards to the inhibition of BTK.6

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Route of elimination

After administration of a single 100 mg radiolabelled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine.6 An irradiated dose of acalabrutinib was 34.7% recovered as the metabolite ACP-5862; 8.6% was recovered as unchanged acalabrutinub; 10.8 was recovered as a mixture of the M7, M8, M9, M10, and M11 metabolites; 5.9% was the M25 metabolite; 2.5% was recovered as the M3 metabolite.3

Half-life

After administering a single oral dose of 100 mg acalabrutinib, the median terminal elimination half-life of the drug was found to be 0.9 (with a range of 0.6 to 2.8) hours.6

The half-life of the active metabolite, ACP-5862, is about 6.9 hours.6

Clearance

Acalabrutinib's mean apparent oral clearance (CL/F) is observed to be 159 L/hr with similar PK between patients and healthy subjects, based on population PK analysis.6

Adverse Effects
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Toxicity

Data regarding the toxicity of acalabrutinib is not readily available.6

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Acalabrutinib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Acalabrutinib can be increased when combined with Abatacept.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Acalabrutinib.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Acalabrutinib.
AcetaminophenThe metabolism of Acalabrutinib can be increased when combined with Acetaminophen.
Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of acalabrutinib. Dose adjustment may be necessary if co-administered.
  • Exercise caution with St. John's Wort. The official product labeling recommends avoiding strong CYP3A4 inducers. This herb induces CYP3A metabolism and may reduce serum levels of acalabrutinib.
  • Take separate from antacids. Take at least 2 hours before or after antacids.
  • Take with a full glass of water.
  • Take with or without food.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
CalquenceCapsule100 mgOralAstra Zeneca Ab2020-12-16Not applicableEU flag
CalquenceCapsule100 mgOralAstra Zeneca2019-10-02Not applicableCanada flag
CalquenceTablet, film coated100 mgOralAstra Zeneca Ab2023-04-04Not applicableEU flag
CalquenceCapsule100 mgOralAstra Zeneca Ab2020-12-16Not applicableEU flag
CalquenceCapsule, gelatin coated100 mg/1OralAstraZeneca Pharmaceuticals LP2017-10-31Not applicableUS flag

Categories

ATC Codes
L01EL02 — Acalabrutinib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenylimidazoles. These are polycyclic aromatic compounds containing a benzene ring linked to an imidazole ring through a CC or CN bond.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azoles
Sub Class
Imidazoles
Direct Parent
Phenylimidazoles
Alternative Parents
Benzamides / Imidazo[1,5-a]pyrazines / Benzoyl derivatives / N-acylpyrrolidines / Aminopyrazines / N-substituted imidazoles / Imidolactams / Pyridines and derivatives / Heteroaromatic compounds / Tertiary carboxylic acid amides
show 7 more
Substituents
4-phenylimidazole / 5-phenylimidazole / Amine / Amino acid or derivatives / Aminopyrazine / Aromatic heteropolycyclic compound / Azacycle / Benzamide / Benzenoid / Benzoic acid or derivatives
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
I42748ELQW
CAS number
1420477-60-6
InChI Key
WDENQIQQYWYTPO-IBGZPJMESA-N
InChI
InChI=1S/C26H23N7O2/c1-2-6-21(34)32-15-5-7-19(32)25-31-22(23-24(27)29-14-16-33(23)25)17-9-11-18(12-10-17)26(35)30-20-8-3-4-13-28-20/h3-4,8-14,16,19H,5,7,15H2,1H3,(H2,27,29)(H,28,30,35)/t19-/m0/s1
IUPAC Name
4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide
SMILES
CC#CC(=O)N1CCC[C@H]1C1=NC(=C2N1C=CN=C2N)C1=CC=C(C=C1)C(=O)NC1=CC=CC=N1

References

General References
  1. Wu J, Zhang M, Liu D: Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016 Mar 9;9:21. doi: 10.1186/s13045-016-0250-9. [Article]
  2. Cheah CY, Seymour JF, Wang ML: Mantle Cell Lymphoma. J Clin Oncol. 2016 Apr 10;34(11):1256-69. doi: 10.1200/JCO.2015.63.5904. Epub 2016 Jan 11. [Article]
  3. Podoll T, Pearson PG, Evarts J, Ingallinera T, Bibikova E, Sun H, Gohdes M, Cardinal K, Sanghvi M, Slatter JG: Bioavailability, Biotransformation, and Excretion of the Covalent Bruton Tyrosine Kinase Inhibitor Acalabrutinib in Rats, Dogs, and Humans. Drug Metab Dispos. 2019 Feb;47(2):145-154. doi: 10.1124/dmd.118.084459. Epub 2018 Nov 15. [Article]
  4. Lymphoma Research Foundation's Getting the Facts: Mantle Cell Lymphoma - Relapsed/Refractory [Link]
  5. Astra Zeneca Press Release: US FDA Approves Astrazeneca's Calquence for Adult Patients with Previously-Treated Mantle Cell Lymphoma [Link]
  6. FDA Approved Drug Products: Calquence Acalabrutinib Oral Capsules [Link]
  7. FDA Approved Drug Products: Calquence (acalabrutinib) tablets for oral use [Link]
  8. Bloomberg: CALQUENCE (acalabrutinib) tablet formulation approved in the US across current indications [Link]
PubChem Compound
71226662
PubChem Substance
347828068
ChemSpider
36764951
BindingDB
50175583
RxNav
1986808
ChEBI
167707
ChEMBL
CHEMBL3707348
ZINC
ZINC000208774715
PDBe Ligand
XQQ
Wikipedia
Acalabrutinib
PDB Entries
8fd9
FDA label
Download (492 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentChronic Lymphocytic Leukemia and Relapsed and Refractory Mantle Cell Lymphoma1
3Active Not RecruitingTreatmentChronic Lymphocytic Leukemia5
3Active Not RecruitingTreatmentChronic Lymphocytic Leukemia- Binet Staging System1
3Active Not RecruitingTreatmentDiffuse Large B-Cell Lymphoma (DLBCL)1
3Active Not RecruitingTreatmentMantle Cell Lymphoma (MCL)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral100 mg
Capsule, gelatin coatedOral100 mg/1
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral100 mg
Capsule, coatedOral100 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9796721No2017-10-242036-07-01US flag
US9758524No2017-09-122032-07-11US flag
US9290504No2016-03-222032-07-11US flag
US7459554No2008-12-022026-11-24US flag
US10167291No2019-01-012036-07-01US flag
US10272083No2019-04-302035-01-21US flag
US10239883No2019-03-262032-07-11US flag
US11059829No2021-07-132036-07-01US flag
US11771696No2015-01-212035-01-21US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityFreely soluble in water at pH values below 3 but is practically insoluble in water at pH values above 6FDA Label
logP0.49ChemSpider
Predicted Properties
PropertyValueSource
Water Solubility0.0109 mg/mLALOGPS
logP2.69ALOGPS
logP2.56Chemaxon
logS-4.6ALOGPS
pKa (Strongest Acidic)12.34Chemaxon
pKa (Strongest Basic)5Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area118.51 Å2Chemaxon
Rotatable Bond Count5Chemaxon
Refractivity135.72 m3·mol-1Chemaxon
Polarizability51 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-0009100000-1a9cd814020eb48227c0
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-03k9-0001900000-ab75d44782140dab6c84
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-05fr-0009100000-9dcaefad44b121c78046
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-01p6-3002900000-3712512f3b94661751f5
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-001a-2059200000-f26af6f03d638dad5032
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0f96-7039400000-6d5b629265d744b5e69e
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-195.473
predicted
DeepCCS 1.0 (2019)
[M+H]+197.86858
predicted
DeepCCS 1.0 (2019)
[M+Na]+203.7811
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein tyrosine kinase activity
Specific Function
Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately le...
Gene Name
BTK
Uniprot ID
Q06187
Uniprot Name
Tyrosine-protein kinase BTK
Molecular Weight
76280.71 Da
References
  1. Bond DA, Woyach JA: Targeting BTK in CLL: Beyond Ibrutinib. Curr Hematol Malig Rep. 2019 Jun;14(3):197-205. doi: 10.1007/s11899-019-00512-0. [Article]
  2. Wilkinson T, Dixon R, Page C, Carroll M, Griffiths G, Ho LP, De Soyza A, Felton T, Lewis KE, Phekoo K, Chalmers JD, Gordon A, McGarvey L, Doherty J, Read RC, Shankar-Hari M, Martinez-Alier N, O'Kelly M, Duncan G, Walles R, Sykes J, Summers C, Singh D: ACCORD: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients: A structured summary of a study protocol for a randomised controlled trial. Trials. 2020 Jul 31;21(1):691. doi: 10.1186/s13063-020-04584-9. [Article]
  3. Castillo JJ, Treon SP: What is new in the treatment of Waldenstrom macroglobulinemia? Leukemia. 2019 Nov;33(11):2555-2562. doi: 10.1038/s41375-019-0592-8. Epub 2019 Oct 7. [Article]
  4. Zheng TJ, Lofurno ER, Melrose AR, Lakshmanan HHS, Pang J, Phillips KG, Fallon ME, Kohs TCL, Ngo ATP, Shatzel JJ, Hinds MT, McCarty OJT, Aslan JE: Assessment of the effects of Syk and BTK inhibitors on GPVI-mediated platelet signaling and function. Am J Physiol Cell Physiol. 2021 May 1;320(5):C902-C915. doi: 10.1152/ajpcell.00296.2020. Epub 2021 Mar 10. [Article]
  5. Kaliamurthi S, Selvaraj G, Selvaraj C, Singh SK, Wei DQ, Peslherbe GH: Structure-Based Virtual Screening Reveals Ibrutinib and Zanubrutinib as Potential Repurposed Drugs against COVID-19. Int J Mol Sci. 2021 Jun 30;22(13). pii: ijms22137071. doi: 10.3390/ijms22137071. [Article]
  6. FDA Approved Drug Products: Calquence Acalabrutinib Oral Capsules [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: Calquence Acalabrutinib Oral Capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. FDA Approved Drug Products: Calquence Acalabrutinib Oral Capsules [Link]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...

Components:
References
  1. FDA Approved Drug Products: Calquence Acalabrutinib Oral Capsules [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Abdelhameed AS, Alanazi AM, Bakheit AH, Hassan ES, Herqash RN, Almutairi FM: Novel BTK inhibitor acalabrutinib (ACP-196) tightly binds to site I of the human serum albumin as observed by spectroscopic and computational studies. Int J Biol Macromol. 2019 Apr 15;127:536-543. doi: 10.1016/j.ijbiomac.2019.01.083. Epub 2019 Jan 18. [Article]
  2. Podoll T, Pearson PG, Evarts J, Ingallinera T, Bibikova E, Sun H, Gohdes M, Cardinal K, Sanghvi M, Slatter JG: Bioavailability, Biotransformation, and Excretion of the Covalent Bruton Tyrosine Kinase Inhibitor Acalabrutinib in Rats, Dogs, and Humans. Drug Metab Dispos. 2019 Feb;47(2):145-154. doi: 10.1124/dmd.118.084459. Epub 2018 Nov 15. [Article]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...

Components:
References
  1. Podoll T, Pearson PG, Evarts J, Ingallinera T, Bibikova E, Sun H, Gohdes M, Cardinal K, Sanghvi M, Slatter JG: Bioavailability, Biotransformation, and Excretion of the Covalent Bruton Tyrosine Kinase Inhibitor Acalabrutinib in Rats, Dogs, and Humans. Drug Metab Dispos. 2019 Feb;47(2):145-154. doi: 10.1124/dmd.118.084459. Epub 2018 Nov 15. [Article]

Drug created at October 20, 2016 20:41 / Updated at March 28, 2024 03:23