Identification

Name
Acalabrutinib
Accession Number
DB11703
Type
Small Molecule
Groups
Approved, Investigational
Description

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) medication as a Bruton Tyrosine Kinase (BTK) inhibitor indicated for the treatment of adult patients with Mantle Cell Lymphoma (MCL) who have already received at least one prior therapy, marking the company's first entry into the treatment of blood cancers.

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 [4].

Structure
Thumb
Synonyms
Not Available
External IDs
ACP-196
Unapproved/Other Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CalquenceCapsule, gelatin coated100 mg/1OralAstra Zeneca Lp2017-10-31Not applicableUs
Categories
UNII
I42748ELQW
CAS number
1420477-60-6
Weight
Average: 465.517
Monoisotopic: 465.191323009
Chemical Formula
C26H23N7O2
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[[email protected]]1C1=NC(=C2N1C=CN=C2N)C1=CC=C(C=C1)C(=O)NC1=CC=CC=N1

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 [FDA Label].

Structured Indications
Pharmacodynamics

When a dosage of acalabrutinib 100 mg twice daily is administered, a median steady state Bruton Tyrosine Kinase (BTK) occupany of approximately ≥ 95% in peripheral blood is maintained over 12 hours allowing for the inactivation of BTK throughout the recommended dosing interval [FDA Label].

Additionally, it has been shown that a single dose of acalabrutinib that is four-fold the maximum recommended single dose (ie. 100 mg) does not appear to prolong QTc interval to any clinically significant extent (ie. ≥ 10 ms) [FDA Label].

Mechanism of action

Mantle Cell Lymphoma (MCL) is a rare yet aggressive type of B-cell non-Hodgkin lymphoma (NHL) with poor prognosis [2, 3]. Subsequently, relapse is common in MCL patients and ultimately represents disease progression [3].

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) [3].

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 [FDA Label].

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, 3]. As a result, acalabrutinib inhibits BTK-mediated activation of downstream signaling proteins CD86 and CD69, which ultimately inhibits malignant B-cell proliferation and survival [3].

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 bystander effects on targets other than BTK.

TargetActionsOrganism
ATyrosine-protein kinase BTK
inhibitor
Human
Absorption

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

Volume of distribution

The mean steady-state volume of distribution is approximately 34 L [FDA Label].

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 [FDA Label].

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 [FDA Label].

Route of elimination

After administration of a single 100 mg radiolabeled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the uring. Less than 1% of the dose was excreted as unchanged acalabrutinib [FDA Label].

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 [FDA Label].

The half-life of the active metabolite, ACP-5862, is about 6.9 hours [FDA Label].

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 [FDA Label].

Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

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. [PubMed:26957112]
  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. [PubMed:26755518]
  3. Lymphoma Research Foundation's Getting the Facts: Mantle Cell Lymphoma - Relapsed/Refractory [Link]
  4. Astra Zeneca Press Release: US FDA Approves Astrazeneca's Calquence for Adult Patients with Previously-Treated Mantle Cell Lymphoma [Link]
External Links
PubChem Compound
71226662
PubChem Substance
347828068
ChemSpider
36764951
ChEMBL
CHEMBL3707348
FDA label
Download (492 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentActivated B-cell Diffuse Large B-Cell Lymphoma (ABC DLBCL)1
1Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)1
1Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Leukemia, Prolymphocytic / Small Lymphocytic Lymphoma (SLL)1
1Active Not RecruitingTreatmentFollicular Lymphoma (FL)1
1Active Not RecruitingTreatmentMultiple Myeloma (MM)1
1RecruitingTreatmentAdvanced B-cell Malignancies1
1, 2Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Leukemia, Prolymphocytic / Richter's Syndrome / Small Lymphocytic Lymphoma (SLL)1
1, 2Not Yet RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)1
1, 2RecruitingTreatmentAgnogenic Myeloid Metaplasia / Chronic Lymphocytic Leukaemia (CLL) / Lymphoma, Hodgkins / Multiple Myeloma (MM) / Non-Hodgkin's Lymphoma (NHL) / Richter's Syndrome / Waldenstrom's Macroglobulinemia (WM)1
1, 2RecruitingTreatmentB-All / Multiple Myeloma (MM) / Non-Hodgkin's Lymphoma (NHL)1
1, 2RecruitingTreatmentGlioblastoma Multiforme1
1, 2RecruitingTreatmentLymphoma, Large B-Cell, Diffuse (DLBCL) / Richter's Syndrome1
2Active Not RecruitingTreatmentCancer, Ovarian1
2Active Not RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2Active Not RecruitingTreatmentMantle Cell Lymphoma (MCL)1
2Active Not RecruitingTreatmentPancreatic Cancer Metastatic1
2Active Not RecruitingTreatmentSquamous Cell Carcinoma of the Head and Neck (SCCHN)1
2Active Not RecruitingTreatmentWaldenstrom's Macroglobulinemia (WM)1
2CompletedTreatmentRheumatoid Arthritis1
2RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)1
2RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL)1
2TerminatedTreatmentPancreatic Cancer Metastatic1
3Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)1
3RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)2
3WithdrawnTreatmentMantle Cell Lymphoma (MCL)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Capsule, gelatin coatedOral100 mg/1
Prices
Not Available
Patents
Not Available

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
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/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
5-phenylimidazole / 4-phenylimidazole / Benzamide / Imidazo[1,5-a]pyrazine / Benzoic acid or derivatives / Benzoyl / N-acylpyrrolidine / Aminopyrazine / Monocyclic benzene moiety / N-substituted imidazole
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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

Drug created on October 20, 2016 14:41 / Updated on December 01, 2017 16:22