U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C26H23N7O2
Molecular Weight 465.5075
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of ACALABRUTINIB

SMILES

CC#CC(=O)N1CCC[C@@]1([H])c2nc(-c3ccc(cc3)C(=O)Nc4ccccn4)c5c(N)nccn52

InChI

InChIKey=WDENQIQQYWYTPO-IBGZPJMESA-N
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

HIDE SMILES / InChI

Molecular Formula C26H23N7O2
Molecular Weight 465.5075
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Acalabrutinib, also known as ACP-196, is a novel irreversible second-generation Bruton’s tyrosine kinase (BTK) inhibitor, which prevents the activation of the B-cell antigen receptor (BCR) signaling pathway and that, was rationally designed to be more potent and selective than ibrutinib. This drug in clinical trials phase III for treatment the treatment of relapsed chronic lymphocytic leukemia. Also in combination with others drugs, Acalabrutinib in phase II of clinical trials for the treatment Glioblastoma Multiforme, Mantle Cell Lymphoma, Squamous Cell Carcinoma of the Head and Neck, Rheumatoid Arthritis and some others.

Approval Year

Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
827 ng/mL
200 mg 2 times / day steady-state, oral
dose: 200 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
ACALABRUTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
323 ng/mL
100 mg 2 times / day multiple, oral
dose: 100 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
ACALABRUTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
1850 ng × h/mL
200 mg 2 times / day steady-state, oral
dose: 200 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
ACALABRUTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
1111 ng × h/mL
100 mg 2 times / day multiple, oral
dose: 100 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
ACALABRUTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
0.6 h
200 mg 2 times / day steady-state, oral
dose: 200 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
ACALABRUTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
0.9 h
100 mg 2 times / day multiple, oral
dose: 100 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
ACALABRUTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
2.5%
100 mg 2 times / day multiple, oral
dose: 100 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
ACALABRUTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
400 mg 1 times / day steady, oral
Highest studied dose
Dose: 400 mg, 1 times / day
Route: oral
Route: steady
Dose: 400 mg, 1 times / day
Sources:
unhealthy, 62 years (range: 44–84 years)
Health Status: unhealthy
Age Group: 62 years (range: 44–84 years)
Sex: M+F
Sources:
100 mg 2 times / day steady, oral
Recommended
Dose: 100 mg, 2 times / day
Route: oral
Route: steady
Dose: 100 mg, 2 times / day
Sources:
unhealthy, adult
Disc. AE: Neoplasms malignant site unspecified NEC, Aortic stenosis...
AEs leading to
discontinuation/dose reduction:
Neoplasms malignant site unspecified NEC (0.2%)
Aortic stenosis (0.2%)
Dyspnea (0.2%)
Leukostasis (0.2%)
Thrombocytopenia (0.5%)
Pulmonary fibrosis (0.2%)
Hemorrhagic bullae (0.2%)
Chest pain (non-cardiac) (0.2%)
Sources:
AEs

AEs

AESignificanceDosePopulation
Aortic stenosis 0.2%
Disc. AE
100 mg 2 times / day steady, oral
Recommended
Dose: 100 mg, 2 times / day
Route: oral
Route: steady
Dose: 100 mg, 2 times / day
Sources:
unhealthy, adult
Chest pain (non-cardiac) 0.2%
Disc. AE
100 mg 2 times / day steady, oral
Recommended
Dose: 100 mg, 2 times / day
Route: oral
Route: steady
Dose: 100 mg, 2 times / day
Sources:
unhealthy, adult
Dyspnea 0.2%
Disc. AE
100 mg 2 times / day steady, oral
Recommended
Dose: 100 mg, 2 times / day
Route: oral
Route: steady
Dose: 100 mg, 2 times / day
Sources:
unhealthy, adult
Hemorrhagic bullae 0.2%
Disc. AE
100 mg 2 times / day steady, oral
Recommended
Dose: 100 mg, 2 times / day
Route: oral
Route: steady
Dose: 100 mg, 2 times / day
Sources:
unhealthy, adult
Leukostasis 0.2%
Disc. AE
100 mg 2 times / day steady, oral
Recommended
Dose: 100 mg, 2 times / day
Route: oral
Route: steady
Dose: 100 mg, 2 times / day
Sources:
unhealthy, adult
Neoplasms malignant site unspecified NEC 0.2%
Disc. AE
100 mg 2 times / day steady, oral
Recommended
Dose: 100 mg, 2 times / day
Route: oral
Route: steady
Dose: 100 mg, 2 times / day
Sources:
unhealthy, adult
Pulmonary fibrosis 0.2%
Disc. AE
100 mg 2 times / day steady, oral
Recommended
Dose: 100 mg, 2 times / day
Route: oral
Route: steady
Dose: 100 mg, 2 times / day
Sources:
unhealthy, adult
Thrombocytopenia 0.5%
Disc. AE
100 mg 2 times / day steady, oral
Recommended
Dose: 100 mg, 2 times / day
Route: oral
Route: steady
Dose: 100 mg, 2 times / day
Sources:
unhealthy, adult
Overview

Overview

Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no [Ki 8.5 uM]
no
no
no
no
no
no
unlikely
unlikely
Comment: acalabrutinib does not inhibit P-gp transporter at clnically relevant concentrations; [I]1/IC50 < 0.1, [I]2/IC50 < 10
Page: 72
weak [Ki 11.3 uM]
weak
weak
weak
weak
likely
Comment: Acalabrutinib is a weak BCRP inhibitor at the intestinal level, per calculations according to FDA Draft Guidance on DDI ([I]1/IC50 < 0.1, [I]2/IC50 = 21); acalabrutinib may increase exposure of BCRP substrates; acalabrutinib may increase methotrexate through inhibition of intestinal BCRP;
Page: 72
yes [Ki 20.6 uM]
yes [Ki 23.9 uM]
yes [Ki 3.3 uM]
yes [Ki 4 uM]
yes [Ki 8.5 uM]
yes
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
no
no
no
no
no
yes
yes
yes
yes
yes (co-administration study)
Comment: itraconazole increased acalabrutinib Cmax by 3.9-fold and AUC by 5.1-fold; rifampin decreased acalabrutinib Cmax by 68% and AUC by 77%
Page: 17
yes
yes (co-administration study)
Comment: ketoconazole abolished 100% of ACP-5862 clearance in human liver microsomes
Page: 62
Tox targets
PubMed

PubMed

TitleDatePubMed
Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia.
2016 Jan 28

Sample Use Guides

for Chronic Lymphocytic Leukemia: 100 to 400 mg once daily in the dose-escalation (phase 1) portion of the study and 100 mg twice daily in the expansion (phase 2) portion.
Route of Administration: Oral
The differential effects of acalabrutinib on primary chronic lymphocytic leukemia (CLL) cells, T cells, NK cells, and epithelial cells were studied by signaling and functional assays. Acalabrutinib inhibited purified ruton’s tyrosine kinase (BTK) with an IC50 of 3 nM and EC50 of 8 nM in a human whole-blood CD69 B cell activation assay. Acalabrutinib was shown to have improved target specificity over ibrutinib with 323-, 94-, 19-, and 9-fold selectivity over the other TEC kinase family members (ITK, TXK, BMX, and TEC, respectively) and no activity against EGFR.
Substance Class Chemical
Created
by admin
on Sat Jun 26 01:03:15 UTC 2021
Edited
by admin
on Sat Jun 26 01:03:15 UTC 2021
Record UNII
I42748ELQW
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
ACALABRUTINIB
INN   USAN   WHO-DD  
USAN   INN  
Official Name English
ACALABRUTINIB [WHO-DD]
Common Name English
ACALABRUTINIB [JAN]
Common Name English
ACP-196
Code English
ACALABRUTINIB [ORANGE BOOK]
Common Name English
BENZAMIDE, 4-(8-AMINO-3-((2S)-1-(1-OXO-2-BUTYN-1-YL)-2-PYRROLIDINYL)IMIDAZO(1,5-A)PYRAZIN-1-YL)-N-2-PYRIDINYL-
Systematic Name English
ACALABRUTINIB [INN]
Common Name English
CALQUENCE
Brand Name English
ACALABRUTINIB [USAN]
Common Name English
ACALABRUTINIB [MI]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C124801
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
NDF-RT N0000175605
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
NCI_THESAURUS C129825
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
EU-Orphan Drug EU/3/16/1625
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
FDA ORPHAN DRUG 489015
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
FDA ORPHAN DRUG 477415
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
FDA ORPHAN DRUG 488915
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
Code System Code Type Description
DRUG BANK
DB11703
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
PRIMARY
NCI_THESAURUS
C113442
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
PRIMARY
CAS
1639823-20-3
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
SUPERSEDED
CAS
1420477-60-6
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
PRIMARY
EVMPD
SUB182073
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
PRIMARY
FDA UNII
I42748ELQW
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
PRIMARY
MERCK INDEX
M12069
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
PRIMARY
LACTMED
Acalabrutinib
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
PRIMARY
RXCUI
1986808
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
PRIMARY
PUBCHEM
71226662
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
PRIMARY
ChEMBL
CHEMBL3707348
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
PRIMARY
INN
10150
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
PRIMARY
DRUG CENTRAL
5260
Created by admin on Sat Jun 26 01:03:15 UTC 2021 , Edited by admin on Sat Jun 26 01:03:15 UTC 2021
PRIMARY
Related Record Type Details
EXCRETED UNCHANGED
In the mass balance study, 84% of the dose was received in the feces and 12% of the dose was recovered in the urine, with less than 1% of the dose excreted as unchanged acalabrutinib in urine.
AMOUNT EXCRETED
URINE
TRANSPORTER -> SUBSTRATE
TARGET -> INHIBITOR
Acalabrutinib forms a covalent bond with Cys481 in the BTK adenosine triphosphate (ATP).
IRREVERSIBLE INHIBITOR
IC50
METABOLIC ENZYME -> SUBSTRATE
OFF TARGET->NON-INHIBITOR
at 10 micromolar 25% inhibition
IC50
TRANSPORTER -> SUBSTRATE
SALT/SOLVATE -> PARENT
BINDER->LIGAND
BINDING
Related Record Type Details
METABOLITE -> PARENT
FECAL
METABOLITE -> PARENT
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Volume of Distribution PHARMACOKINETIC
Biological Half-life PHARMACOKINETIC
Tmax PHARMACOKINETIC ORAL ADMINISTRATION