Capivasertib

Identification

Summary

Capivasertib is a serine/threonine kinase inhibitor used to treat hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer

Brand Names

Truqap

Generic Name

Capivasertib

DrugBank Accession Number

DB12218

Background

Hormone receptor (HR) positive, especially estrogen receptor-positive, HER2-negative breast cancer is the most common subtype of metastatic breast cancer, resulting in more than 400,000 deaths annually. Although endocrine-based therapy is the first line of treatment, resistance eventually emerges, leaving chemotherapy the only but often ineffective treatment left. Therefore, significant research has been put into developing genetically targeted treatments.¹

The PIK3/AKT pathway is one of the most commonly activated pathways in breast cancer, mainly through the constitutively active mutation in AKT1, loss of function mutation in PTEN, a negative regulator of the PIK3/AKT pathway, or PIK3CA mutations. Therefore, targeting the PIK3/AKT pathway presents a promising approach for the treatment of breast cancer, leading to the development of capivasertib, a pan-AKT kinase inhibitor.^1,2,3

On November 17th, 2023, capivasertib, under the brand name TRUQAP, was approved by the FDA for the treatment of adult patients HR-positive, HER2-negative locally advanced or metastatic breast cancer with one or more alterations in PIK3CA/AKT1/PTEN gene(s) in combination with fulvestrant. This approval is based on favorable results obtained from the CAPItello-291 trial, where the combination of capivasertib and fulvestrant reduced the risk of disease progression or death by 50% versus fulvestrant alone.⁵

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

Download

MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Capivasertib (DB12218)

×

Close

Weight

Average: 428.915
Monoisotopic: 428.172751781

Chemical Formula

C₂₁H₂₅ClN₆O₂

Synonyms

• Capivasertib
• Capivasertibum

External IDs

• AZD 5363
• AZD-5363
• AZD5363

Poor quality drug data slowing you down?

Unlock 38% more drug discovery time and eliminate decision-making doubts with this one-stop guide to quality drug data.

Download eBook

Poor quality drug data slowing you down?

Download eBook

Pharmacology

Indication

Capivasertib, in combination with fulvestrant, is indicated for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alteration as detected by an FDA-approved test following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.⁴

Reduce drug development failure rates

Build, train, & validate machine-learning models
with evidence-based and structured datasets.

See how

Build, train, & validate predictive machine-learning models with structured datasets.

See how

Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Used in combination to treat	Metastatic or locally advanced breast cancer	Regimen in combination with: Fulvestrant (DB00947)	••••••••••••	•••••	••••••• •••••••••• •• •• •••••• •• •••••• •• •••••••••• •••••••• •••••••• ••••••• ••••••••••• ••••• ••••••••• ••••• •••••••	••••••

Create Account

Contraindications & Blackbox Warnings

Prevent Adverse Drug Events Today

Tap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.

Learn more

Avoid life-threatening adverse drug events with our Clinical API

Learn more

Pharmacodynamics

In vitro, capivasertib reduced the growth of breast cancer cell lines including those with relevant PIK3CA or AKT1 mutations or PTEN alteration. In vivo, capivasertib alone and in combination with fulvestrant inhibited tumor growth of mouse xenograft models including estrogen receptor-positive breast cancer models with alterations in PIK3CA, AKT1, and PTEN.⁴

The exposure-response relationship and time course of pharmacodynamic response for the effectiveness of capivasertib has not been fully characterized. Exposure-response relationships were observed for diarrhea (CTCAE Grade 2 to 4), rash (CTCAE Grade 2 to 4), and hyperglycemia (CTCAE Grades 3 or 4) at doses of 80 to 800 mg (0.2 to 2 times the approved recommended dosage).⁴

At the recommended capivasertib dose, a mean increase in the QTc interval > 20 ms was not observed.⁴

Mechanism of action

Capivasertib is an inhibitor of all 3 isoforms of serine/threonine kinase AKT (AKT1, AKT2, and AKT3) and inhibits phosphorylation of downstream AKT substrates. AKT activation in tumors is a result of activation of upstream signaling pathways, mutations in AKT1, loss of phosphatase and tensin homolog (PTEN) function, and mutations in the catalytic subunit alpha of phosphatidylinositol 3-kinase (PIK3CA).⁴

Target	Actions	Organism
ARAC-alpha serine/threonine-protein kinase	inhibitor	Humans
ARAC-beta serine/threonine-protein kinase	inhibitor	Humans
ARAC-gamma serine/threonine-protein kinase	inhibitor	Humans

Absorption

The capivasertib steady-state AUC is 8,069 h·ng/mL (37%) and C_max is 1,371 ng/mL (30%). Steady-state concentrations are predicted to be attained on the 3rd and 4th dosing day of each week, starting week 2.⁴

Capivasertib plasma concentrations are approximately 0.5% to 15% of the steady-state Cmax during the off-dosing days.⁴

Capivasertib AUC and C_max are proportional with doses over a range of 80 to 800 mg (0.2 to 2 times the approved recommended dosage).⁴

T_max is approximately 1-2 hours. The absolute bioavailability is 29%.⁴

No clinically meaningful differences in capivasertib pharmacokinetics were observed following the administration of capivasertib with a high-fat meal (approximately 1,000 kcal; fat 60%) or a low-fat meal (approximately 400 kcal; fat 26%).⁴

Volume of distribution

The steady-state oral volume of distribution is 1,847 L (36%).⁴

Protein binding

Capivasertib plasma protein binding is 22% and the plasma-to-blood ratio is 0.71.⁴

Metabolism

Capivasertib is primarily metabolized by CYP3A4 and UGT2B7.⁴

Route of elimination

Following a single radiolabeled oral dose of 400 mg, the mean total recovery was 45% from urine and 50% from feces.⁴

Half-life

The half-life of capivasertib is 8.3 hours.⁴

Clearance

The steady-state oral clearance of capivasertib is 50 L/h (37% CV), and renal clearance was 21% of total clearance.⁴

Adverse Effects

Improve decision support & research outcomes

With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!

See the data

Improve decision support & research outcomes with our structured adverse effects data.

See a data sample

Toxicity

Based on findings in animals and mechanism of action, capivasertib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of capivasertib in pregnant women. In an animal reproduction study, oral administration of capivasertib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality and reduced fetal weights at maternal exposures 0.7 times the human exposure (AUC) at the recommended dose of 400 mg twice daily. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.⁴

Carcinogenicity studies have not been conducted with capivasertib. Capivasertib was genotoxic in the in vivo rat bone marrow micronucleus assay through an aneugenic mechanism. Capivasertib was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay or mouse lymphoma gene mutation assay.⁴

In repeat-dose toxicity studies up to 26 weeks duration in rats and 39 weeks duration in dogs, tubular degeneration in the testes and cellular debris in the epididymides were observed at oral capivasertib doses of 100 mg/kg/day in rats and 15 mg/kg/day in dogs (approximately 1 time the human exposure at the recommended dose of 400 mg twice daily based on AUC). In a male fertility study, capivasertib had no effect on fertility in male rats at oral doses up to 100 mg/kg/day following 10 weeks of treatment. Effects of capivasertib on female fertility have not been studied in animals.⁴

Pathways

Not Available

Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
Integrate drug-drug interactions in your software
Abametapir	The serum concentration of Capivasertib can be increased when it is combined with Abametapir.
Abemaciclib	The excretion of Abemaciclib can be decreased when combined with Capivasertib.
Acamprosate	The excretion of Acamprosate can be decreased when combined with Capivasertib.
Acyclovir	The excretion of Acyclovir can be decreased when combined with Capivasertib.
Afatinib	Capivasertib may decrease the excretion rate of Afatinib which could result in a higher serum level.

Food Interactions

• Take with or without food.

Products

Drug product information from 10+ global regions

Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.

Access now

Access drug product information from over 10 global regions.

Access now

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Truqap	Tablet, film coated	160 mg/1	Oral	AstraZeneca Pharmaceuticals LP	2023-11-16	Not applicable
Truqap	Tablet, film coated	200 mg/1	Oral	AstraZeneca Pharmaceuticals LP	2023-11-16	Not applicable

Categories

Drug Categories

• BCRP/ABCG2 Inhibitors
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• MATE 1 Inhibitors
• MATE 2 Inhibitors
• MATE inhibitors
• OAT3/SLC22A8 Inhibitors
• OATP1B1/SLCO1B1 Inhibitors
• OATP1B3 inhibitors
• OCT2 Inhibitors
• Proto-Oncogene Proteins c-akt, antagonists & inhibitors
• UGT2B7 substrates

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as alpha amino acid amides. These are amide derivatives of alpha amino acids.

Kingdom

Organic compounds

Super Class

Organic acids and derivatives

Class

Carboxylic acids and derivatives

Sub Class

Amino acids, peptides, and analogues

Direct Parent

Alpha amino acid amides

Alternative Parents

Pyrrolo[2,3-d]pyrimidines / Piperidinecarboxamides / Dialkylarylamines / Aminopiperidines / Aminopyrimidines and derivatives / Chlorobenzenes / Aryl chlorides / Imidolactams / Pyrroles / Heteroaromatic compounds / Secondary carboxylic acid amides / Azacyclic compounds / Hydrocarbon derivatives / Monoalkylamines / Carbonyl compounds / Organic oxides / Organochlorides / Organopnictogen compounds / Primary alcohols

show 9 more

Substituents

4-aminopiperidine / Alcohol / Alpha-amino acid amide / Amine / Aminopyrimidine / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Carbonyl group / Carboxamide group / Chlorobenzene / Dialkylarylamine / Halobenzene / Heteroaromatic compound / Hydrocarbon derivative / Imidolactam / Monocyclic benzene moiety / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organochloride / Organohalogen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Piperidine / Piperidinecarboxamide / Primary alcohol / Primary aliphatic amine / Primary amine / Pyrimidine / Pyrrole / Pyrrolo[2,3-d]pyrimidine / Pyrrolopyrimidine / Secondary carboxylic acid amide

show 28 more

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Affected organisms

Not Available

Chemical Identifiers

UNII

WFR23M21IE

CAS number

1143532-39-1

InChI Key

JDUBGYFRJFOXQC-KRWDZBQOSA-N

InChI

InChI=1S/C21H25ClN6O2/c22-15-3-1-14(2-4-15)17(6-12-29)27-20(30)21(23)7-10-28(11-8-21)19-16-5-9-24-18(16)25-13-26-19/h1-5,9,13,17,29H,6-8,10-12,23H2,(H,27,30)(H,24,25,26)/t17-/m0/s1

IUPAC Name

4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperidine-4-carboxamide

SMILES

NC1(CCN(CC1)C1=C2C=CNC2=NC=N1)C(=O)N[C@@H](CCO)C1=CC=C(Cl)C=C1

References

General References

1. Smyth LM, Tamura K, Oliveira M, Ciruelos EM, Mayer IA, Sablin MP, Biganzoli L, Ambrose HJ, Ashton J, Barnicle A, Cashell DD, Corcoran C, de Bruin EC, Foxley A, Hauser J, Lindemann JPO, Maudsley R, McEwen R, Moschetta M, Pass M, Rowlands V, Schiavon G, Banerji U, Scaltriti M, Taylor BS, Chandarlapaty S, Baselga J, Hyman DM: Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1 (E17K)-Mutant, ER-Positive Metastatic Breast Cancer. Clin Cancer Res. 2020 Aug 1;26(15):3947-3957. doi: 10.1158/1078-0432.CCR-19-3953. Epub 2020 Apr 20. [Article]
2. Smyth LM, Batist G, Meric-Bernstam F, Kabos P, Spanggaard I, Lluch A, Jhaveri K, Varga A, Wong A, Schram AM, Ambrose H, Carr TH, de Bruin EC, Salinas-Souza C, Foxley A, Hauser J, Lindemann JPO, Maudsley R, McEwen R, Moschetta M, Nikolaou M, Schiavon G, Razavi P, Banerji U, Baselga J, Hyman DM, Chandarlapaty S: Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer. NPJ Breast Cancer. 2021 Apr 16;7(1):44. doi: 10.1038/s41523-021-00251-7. [Article]
3. Andrikopoulou A, Chatzinikolaou S, Panourgias E, Kaparelou M, Liontos M, Dimopoulos MA, Zagouri F: "The emerging role of capivasertib in breast cancer". Breast. 2022 Jun;63:157-167. doi: 10.1016/j.breast.2022.03.018. Epub 2022 Apr 1. [Article]
4. FDA Approved Drug Products: TRUQAP™ (capivasertib) tablets, for oral use (November 2023) [Link]
5. Truqap Plus Fulvestrant Approved for HR-Positive Advanced Breast Cancer [Link]

External Links

PubChem Compound

25227436

PubChem Substance

347828497

ChemSpider

28189073

BindingDB

50427349

RxNav

2669967

ChEMBL

CHEMBL2325741

ZINC

ZINC000043204023

PDBe Ligand

0XZ

Wikipedia

Capivasertib

PDB Entries

4gv1

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Hormone Sensitive Prostate Cancer	1
3	Active Not Recruiting	Treatment	Locally Advanced (Inoperable) or Metastatic Breast Cancer	1
3	Active Not Recruiting	Treatment	Triple-Negative Breast Neoplasm	1
3	Recruiting	Treatment	Locally Advanced (Inoperable) or Metastatic Breast Cancer	1
3	Recruiting	Treatment	Metastatic Castration-Resistant Prostate Cancer (mCRPC) / Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, film coated	Oral	160 mg/1
Tablet, film coated	Oral	200 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US11760760	No	2008-10-10	2028-10-10
US10654855	No	2008-10-10	2028-10-10
US10039766	No	2013-04-16	2033-04-16
US8809336	No	2005-10-25	2025-10-25
US8101623	No	2010-03-10	2030-03-10
US9006430	No	2005-10-25	2025-10-25
US10059714	No	2008-10-10	2028-10-10
US9487525	No	2013-04-16	2033-04-16

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Freely soluble	https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/841065f2-fcba-4795-b92a-3afc2ba47325/841065f2-fcba-4795-b92a-3afc2ba47325_viewable_rendition__v.pdf

Predicted Properties

Property	Value	Source
logP	1.31	Chemaxon
pKa (Strongest Acidic)	13.03	Chemaxon
pKa (Strongest Basic)	8.33	Chemaxon
Physiological Charge	2	Chemaxon
Hydrogen Acceptor Count	6	Chemaxon
Hydrogen Donor Count	4	Chemaxon
Polar Surface Area	120.16 Å2	Chemaxon
Rotatable Bond Count	6	Chemaxon
Refractivity	116.97 m3·mol-1	Chemaxon
Polarizability	44.79 Å3	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-004i-0010900000-e4bf4677e71ed31040e0
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0a6s-0244900000-94f2183b797568a3858b
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-00ke-0294300000-948e302d2f9d0479d1b4
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0a4l-2391300000-bedd88e264f95a3806cc
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-00mp-0192100000-1dbc85ea361a1bcdc958
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0006-9683200000-93ebcbe8247b9ad80b9a
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	202.98112	predicted	DeepCCS 1.0 (2019)
[M+H]+	205.33913	predicted	DeepCCS 1.0 (2019)
[M+Na]+	211.43227	predicted	DeepCCS 1.0 (2019)

Targets

Build, predict & validate machine-learning models

Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.

Learn more

Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.

Learn more

Details1. RAC-alpha serine/threonine-protein kinase

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Protein serine/threonine/tyrosine kinase activity

Specific Function

AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, ...

Gene Name

AKT1

Uniprot ID

P31749

Uniprot Name

RAC-alpha serine/threonine-protein kinase

Molecular Weight

55686.035 Da

References

1. FDA Approved Drug Products: TRUQAP™ (capivasertib) tablets, for oral use (November 2023) [Link]

Details2. RAC-beta serine/threonine-protein kinase

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Protein serine/threonine kinase activity

Specific Function

AKT2 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, ...

Gene Name

AKT2

Uniprot ID

P31751

Uniprot Name

RAC-beta serine/threonine-protein kinase

Molecular Weight

55768.32 Da

References

1. FDA Approved Drug Products: TRUQAP™ (capivasertib) tablets, for oral use (November 2023) [Link]

Details3. RAC-gamma serine/threonine-protein kinase

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

AKT3 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT3 is the least studied AKT isoform. It plays an important role in brain development and is crucial for the viability of malignant glioma cells. AKT3 isoform may also be the key molecule in up-regulation and down-regulation of MMP13 via IL13. Required for the coordination of mitochondrial biogenesis with growth factor-induced increases in cellular energy demands. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis.

Specific Function

Atp binding

Gene Name

AKT3

Uniprot ID

Q9Y243

Uniprot Name

RAC-gamma serine/threonine-protein kinase

Molecular Weight

55774.1 Da

References

1. FDA Approved Drug Products: TRUQAP™ (capivasertib) tablets, for oral use (November 2023) [Link]

×

Identify potential medication risks

Easily compare up to 40 drugs with our drug interaction checker.

Get severity rating, description, and management advice.

Learn more

Drug created at October 20, 2016 21:38 / Updated at November 23, 2023 01:36