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Details

Stereochemistry ABSOLUTE
Molecular Formula C26H23N7O2.2H2O
Molecular Weight 501.5371
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of ACALABRUTINIB DIHYDRATE

SMILES

O.O.CC#CC(=O)N1CCC[C@H]1C2=NC(=C3N2C=CN=C3N)C4=CC=C(C=C4)C(=O)NC5=CC=CC=N5

InChI

InChIKey=YDXGIZXBLWJIEC-TXEPZDRESA-N
InChI=1S/C26H23N7O2.2H2O/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);2*1H2/t19-;;/m0../s1

HIDE SMILES / InChI

Molecular Formula H2O
Molecular Weight 18.0153
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Molecular Formula C26H23N7O2
Molecular Weight 465.5065
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

Targets

Targets

Primary TargetPharmacologyConditionPotency
3.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
CALQUENCE

Approved Use

CALQUENCE is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

Launch Date

2017
Primary
Unknown

Approved Use

Unknown
Palliative
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
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
Condition: Relapsed Chronic Lymphocytic Leukemia
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: Page: p. 132
unhealthy, adult
n = 610
Health Status: unhealthy
Condition: hematological malignancies
Age Group: adult
Sex: M+F
Population Size: 610
Sources: Page: p. 132
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: Page: p. 132
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: Page: p. 132
unhealthy, adult
n = 610
Health Status: unhealthy
Condition: hematological malignancies
Age Group: adult
Sex: M+F
Population Size: 610
Sources: Page: p. 132
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: Page: p. 132
unhealthy, adult
n = 610
Health Status: unhealthy
Condition: hematological malignancies
Age Group: adult
Sex: M+F
Population Size: 610
Sources: Page: p. 132
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: Page: p. 132
unhealthy, adult
n = 610
Health Status: unhealthy
Condition: hematological malignancies
Age Group: adult
Sex: M+F
Population Size: 610
Sources: Page: p. 132
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: Page: p. 132
unhealthy, adult
n = 610
Health Status: unhealthy
Condition: hematological malignancies
Age Group: adult
Sex: M+F
Population Size: 610
Sources: Page: p. 132
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: Page: p. 132
unhealthy, adult
n = 610
Health Status: unhealthy
Condition: hematological malignancies
Age Group: adult
Sex: M+F
Population Size: 610
Sources: Page: p. 132
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: Page: p. 132
unhealthy, adult
n = 610
Health Status: unhealthy
Condition: hematological malignancies
Age Group: adult
Sex: M+F
Population Size: 610
Sources: Page: p. 132
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: Page: p. 132
unhealthy, adult
n = 610
Health Status: unhealthy
Condition: hematological malignancies
Age Group: adult
Sex: M+F
Population Size: 610
Sources: Page: p. 132
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: Page: p. 132
unhealthy, adult
n = 610
Health Status: unhealthy
Condition: hematological malignancies
Age Group: adult
Sex: M+F
Population Size: 610
Sources: Page: p. 132
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: 72.0
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: 72.0
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: 17.0
yes
yes (co-administration study)
Comment: ketoconazole abolished 100% of ACP-5862 clearance in human liver microsomes
Page: 62.0
Tox targets
PubMed

PubMed

TitleDatePubMed

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 Dec 16 19:06:08 GMT 2023
Edited
by admin
on Sat Dec 16 19:06:08 GMT 2023
Record UNII
F86EN73XQR
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
ACALABRUTINIB DIHYDRATE
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-, HYDRATE (1:2)
Common Name English
Code System Code Type Description
CAS
2648852-74-6
Created by admin on Sat Dec 16 19:06:09 GMT 2023 , Edited by admin on Sat Dec 16 19:06:09 GMT 2023
PRIMARY
PUBCHEM
156749065
Created by admin on Sat Dec 16 19:06:09 GMT 2023 , Edited by admin on Sat Dec 16 19:06:09 GMT 2023
PRIMARY
FDA UNII
F86EN73XQR
Created by admin on Sat Dec 16 19:06:09 GMT 2023 , Edited by admin on Sat Dec 16 19:06:09 GMT 2023
PRIMARY
Related Record Type Details
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ANHYDROUS->SOLVATE