Avatrombopag

Identification

Name

Avatrombopag

Accession Number

DB11995

Description

Avatrombopag (Doptelet), is an orally administered, small-molecule thrombopoietin receptor (c-Mpl) agonist which increases platelet number, but not platelet activation ³, ¹⁰. This decreases the need for blood transfusions ¹⁰.

Patients with thrombocytopenia and chronic liver disease (leading to thrombocytopenia) often require platelet transfusions before surgical procedures to decrease the risk of bleeding ¹. Thrombocytopenia (or decreased numbers of platelets) is a common complication in patients suffering from chronic liver disease, either as an immediate result of liver disease or a consequence of interferon-based antiviral therapy ¹⁶.

Avatrombopag was approved by the FDA on May 21, 2018 for thrombocytopenia (low platelets) in adults with chronic liver disease who are scheduled to undergo a procedure ¹⁴. It is administered orally as avatrombopag maleate, its salt form ¹¹.

Doptelet (Avatrombopag) is the first orally administered treatment option for patients with chronic liver disease, allowing a large population of patients to avoid a platelet transfusion before a procedure by increasing platelet counts to the optimal level of greater or equal to 50,000 per microliter ¹⁵.

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Avatrombopag (DB11995)

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Weight

Average: 649.65
Monoisotopic: 648.1510867

Chemical Formula

C₂₉H₃₄Cl₂N₆O₃S₂

Synonyms

• Avatrombopag

External IDs

• E5501
• YM-477

Pharmacology

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Indication

Indicated for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure ^Label.

Associated Conditions

• Thrombocytopenia

Contraindications & Blackbox Warnings

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Pharmacodynamics

In a study of efficacy, avatrombopag resulted in dose and exposure-dependent elevations in platelet counts in adults ¹. The onset of the platelet count increase was noted within 3 to 5 days of the start of a 5-day treatment course, with the highest level of effect measured after 10 to 13 days. Following this, platelet counts decreased gradually, returning to near baseline values at the 35-day point ^Label.

Increased platelet activation leads to increased blood clotting, which may lead to various complications ⁴. Avatrombopag does not lead to increased platelet activation ¹⁰.

Mechanism of action

Avatrombopag is an orally bioavailable, small molecule thrombopoietin (TPO) receptor agonist that stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells resulting in an increased production of platelets. Avatrombopag is not competitive with thrombopoietin for binding to the TPO receptor and has an additive pharmacological effect with TPO on platelet production ^Label.

Avatrombopag is a thrombopoietin receptor (TPOR; MPL) agonist, with possible megakaryopoiesis stimulating activity. After administration, avatrombopag binds to and stimulates the platelet thrombopoeitin receptor (TPOR), which can lead to the proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. This process increases the production of platelets and may serve to prevent chemotherapy-induced thrombocytopenia (CIT). TPOR is classified as a cytokine receptor and as a member of the hematopoietin receptor superfamily ¹².

Target	Actions	Organism
UATP-binding cassette sub-family G member 2	inhibitor	Humans
AThrombopoietin receptor	agonist	Humans
USolute carrier family 22 member 8	inhibitor	Humans

Absorption

Following single dosing under fasted and fed conditions, mean peak concentrations occurred at 5-8 hours and declined with a half-life of 16-18 hours in Japanese and white subjects. Administration with food did not have an effect on the rate or extent of avatrombopag absorption, however, significantly reduced pharmacokinetic variability relative to the fasting state ³.

Avatrombopag showed dose-proportional pharmacokinetics after single doses from 10 mg (0.25-times the lowest approved dosage) to 80 mg (1.3-times the highest recommended dosage). Healthy subjects administered 40 mg of avatrombopag showed a geometric mean (%CV) maximal concentration (Cmax) of 166 (84%) ng/mL and area under the time-concentration curve, extrapolated to infinity (AUC0-inf) of 4198 (83%) ng.hr/mL. The pharmacokinetics of avatrombopag are similar in both healthy subjects and the chronic liver disease population ^Label.

Volume of distribution

Avatrombopag has an estimated mean volume of distribution (%CV) of 180 L (25%) ^Label.

Protein binding

Avatrombopag is greater than 96% bound to human plasma proteins ^Label.

Metabolism

Avatrombopag is primarily metabolized by cytochrome P450 (CYP) 2C9 and CYP3A4 ^Label.

Route of elimination

Fecal excretion accounted for 88% of the administered dose, with 34% of the dose excreted as unchanged avatrombopag. Only 6% of the administered dose was found in urine ^Label.

Half-life

The mean plasma elimination half-life (%CV) of avatrombopag is approximately 19 hours (19%) ^Label.

Clearance

The mean (%CV) of the clearance of avatrombopag is estimated to be 6.9 L/hr (29%) ^Label.

Adverse Effects

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Toxicity

The most common adverse reactions reported in at least 3% of patients were pyrexia, abdominal pain, nausea, headache, fatigue, and peripheral edema ⁹, ^Label. Hyponatremia was also a rare serious adverse effect of this drug, seen in only 2 patients in the treatment group ^Label. Adverse reactions resulting in discontinuation of this drug have been anemia, pyrexia, and myalgia ^Label.

Atrombopag is a thrombopoietin (TPO) receptor agonist, and TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease. Portal venous thrombosis occurrence has been reported in patients with chronic liver disease who are treated with TPO receptor agonists ^Label. Patients should be monitored carefully ¹³.

Affected organisms

• Humans and other mammals

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.

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

Drug	Interaction
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Abemaciclib	Avatrombopag may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Acenocoumarol	The metabolism of Acenocoumarol can be increased when combined with Avatrombopag.
Acetohexamide	The metabolism of Acetohexamide can be increased when combined with Avatrombopag.
Acetylsalicylic acid	The metabolism of Acetylsalicylic acid can be increased when combined with Avatrombopag.
Acyclovir	The excretion of Acyclovir can be decreased when combined with Avatrombopag.
Afatinib	The serum concentration of Avatrombopag can be increased when it is combined with Afatinib.
Allopurinol	Avatrombopag may decrease the excretion rate of Allopurinol which could result in a higher serum level.
Almotriptan	The metabolism of Almotriptan can be increased when combined with Avatrombopag.
Alosetron	The metabolism of Alosetron can be increased when combined with Avatrombopag.
Alpelisib	The serum concentration of Alpelisib can be increased when it is combined with Avatrombopag.

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Food Interactions

• Take with food.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Avatrombopag maleate	GDW7M2P1IS	677007-74-8	MISPBGHDNZYFNM-BTJKTKAUSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Doptelet	Tablet, film coated	20 mg	Oral	SWEDISH ORPHAN BIOVITRUM AB (PUBL)	2021-01-28	Not applicable
Doptelet	Tablet, film coated	20 mg/1	Oral	AkaRx, Inc.	2018-05-23	Not applicable
Doptelet	Tablet, film coated	20 mg	Oral	SWEDISH ORPHAN BIOVITRUM AB (PUBL)	2020-12-16	Not applicable
Doptelet	Tablet, film coated	20 mg	Oral	SWEDISH ORPHAN BIOVITRUM AB (PUBL)	2020-12-16	Not applicable

Categories

ATC Codes

B02BX08 — Avatrombopag

• B02BX — Other systemic hemostatics
• B02B — VITAMIN K AND OTHER HEMOSTATICS
• B02 — ANTIHEMORRHAGICS
• B — BLOOD AND BLOOD FORMING ORGANS

Drug Categories

• BCRP/ABCG2 Inhibitors
• Blood and Blood Forming Organs
• Cytochrome P-450 CYP2C8 Inducers
• Cytochrome P-450 CYP2C8 Inducers (weak)
• Cytochrome P-450 CYP2C9 Inducers
• Cytochrome P-450 CYP2C9 Inducers (weak)
• Cytochrome P-450 Enzyme Inducers
• Hemostatics
• OAT3/SLC22A8 Inhibitors
• P-glycoprotein substrates
• Receptors, Thrombopoietin, agonists
• Sulfur Compounds

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as n-arylpiperazines. These are organic compounds containing a piperazine ring where the nitrogen ring atom carries an aryl group.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Diazinanes

Sub Class

Piperazines

Direct Parent

N-arylpiperazines

Alternative Parents

Nicotinamides / Piperidinecarboxylic acids / Dialkylarylamines / 2,4,5-trisubstituted thiazoles / Cyclohexylamines / Aminopyridines and derivatives / N-alkylpiperazines / Aminothiazoles / Imidolactams / Aryl chlorides / Heteroaromatic compounds / Thiophenes / Trialkylamines / Amino acids / Secondary carboxylic acid amides / Monocarboxylic acids and derivatives / Azacyclic compounds / Carboxylic acids / Carbonyl compounds / Hydrocarbon derivatives / Organic oxides / Organochlorides

show 12 more

Substituents

1,3-thiazolamine / 2,4,5-trisubstituted 1,3-thiazole / Amine / Amino acid / Amino acid or derivatives / Aminopyridine / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Azole / Carbonyl group / Carboxamide group / Carboxylic acid / Carboxylic acid derivative / Cyclohexylamine / Dialkylarylamine / Heteroaromatic compound / Hydrocarbon derivative / Imidolactam / Monocarboxylic acid or derivatives / N-alkylpiperazine / N-arylpiperazine / Nicotinamide / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organochloride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Piperidine / Piperidinecarboxylic acid / Pyridine / Pyridine carboxylic acid or derivatives / Secondary carboxylic acid amide / Tertiary aliphatic amine / Tertiary amine / Thiazole / Thiophene

show 30 more

Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

Not Available

Chemical Identifiers

UNII

3H8GSZ4SQL

CAS number

570406-98-3

InChI Key

OFZJKCQENFPZBH-UHFFFAOYSA-N

InChI

InChI=1S/C29H34Cl2N6O3S2/c30-20-15-23(41-17-20)24-27(37-12-10-35(11-13-37)21-4-2-1-3-5-21)42-29(33-24)34-26(38)19-14-22(31)25(32-16-19)36-8-6-18(7-9-36)28(39)40/h14-18,21H,1-13H2,(H,39,40)(H,33,34,38)

IUPAC Name

1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)-1,3-thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid

SMILES

OC(=O)C1CCN(CC1)C1=C(Cl)C=C(C=N1)C(=O)NC1=NC(C2=CC(Cl)=CS2)=C(S1)N1CCN(CC1)C1CCCCC1

References

General References

1. Terrault N, Chen YC, Izumi N, Kayali Z, Mitrut P, Tak WY, Allen LF, Hassanein T: Avatrombopag Before Procedures Reduces Need for Platelet Transfusion in Patients With Chronic Liver Disease and Thrombocytopenia. Gastroenterology. 2018 May 17. pii: S0016-5085(18)34545-1. doi: 10.1053/j.gastro.2018.05.025. [PubMed:29778606]
2. Qureshi K, Patel S, Meillier A: The Use of Thrombopoietin Receptor Agonists for Correction of Thrombocytopenia prior to Elective Procedures in Chronic Liver Diseases: Review of Current Evidence. Int J Hepatol. 2016;2016:1802932. doi: 10.1155/2016/1802932. Epub 2016 Oct 9. [PubMed:27800187]
3. Nomoto M, Pastino G, Rege B, Aluri J, Ferry J, Han D: Pharmacokinetics, Pharmacodynamics, Pharmacogenomics, Safety, and Tolerability of Avatrombopag in Healthy Japanese and White Subjects. Clin Pharmacol Drug Dev. 2018 Feb;7(2):188-195. doi: 10.1002/cpdd.349. Epub 2017 Mar 24. [PubMed:28339166]
4. Yun SH, Sim EH, Goh RY, Park JI, Han JY: Platelet Activation: The Mechanisms and Potential Biomarkers. Biomed Res Int. 2016;2016:9060143. doi: 10.1155/2016/9060143. Epub 2016 Jun 15. [PubMed:27403440]
5. Bussel JB, Kuter DJ, Aledort LM, Kessler CM, Cuker A, Pendergrass KB, Tang S, McIntosh J: A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia. Blood. 2014 Jun 19;123(25):3887-94. doi: 10.1182/blood-2013-07-514398. Epub 2014 May 6. [PubMed:24802775]
6. Avotrombopag [Link]
7. FDA Ok's avatrombopag [Link]
8. Avatrombopag [Link]
9. FDA approves avatrombopag for thrombocytopenia in adults with chronic liver disease [Link]
10. Avatrombopag, a Novel Thrombopoietin Receptor Agonist, Increases Platelet Counts without Increasing Platelet Activation in Patients with Thrombocytopenia Due to Chronic Liver Disease [Link]
11. Avotrombopag maleate approval, FDA [Link]
12. NCI Drug Dictionary: Avotrombopag maleate [Link]
13. Drugs.com: Avotrombopag [Link]
14. NEJM Journal Watch: FDA Approval of Avatrombopag [Link]
15. Avatrombopag Gains FDA Approval for Patients with Chronic Liver Disease [Link]
16. NICE UK review document, Avatrombopag [File]

External Links

PubChem Compound

9852519

PubChem Substance

347828315

ChemSpider

8028230

RxNav

2045726

ChEMBL

CHEMBL2103883

ZINC

ZINC000072190218

Wikipedia

Avatrombopag

FDA label

Download (436 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Not Yet Recruiting	Treatment	Immune Thrombocytopenia	1
3	Active Not Recruiting	Supportive Care	Chemotherapy-Induced Thrombocytopenia	1
3	Completed	Treatment	Chronic immune thrombocytopenia / Immune Thrombocytopenia	1
3	Completed	Treatment	Thrombocytopenia Associated With Liver Disease	2
3	Recruiting	Supportive Care	Immune Thrombocytopenia	1
3	Terminated	Treatment	Idiopathic Thrombocytopenic Purpura	1
3	Terminated	Treatment	Thrombocytopenia	1
2	Completed	Treatment	Chronic Idiopathic Thrombocytopenic Purpura / Idiopathic Thrombocytopenic Purpura	1
2	Completed	Treatment	Idiopathic Thrombocytopenic Purpura	1
2	Completed	Treatment	Thrombocytopenia	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, film coated	Oral	20 mg/1
Tablet, film coated	Oral	20 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8765764	No	2014-07-01	2023-01-15
US7638536	No	2009-12-29	2025-05-05
US8338429	No	2012-12-25	2023-06-30

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Insoluble	https://medkoo.com/products/5199

Predicted Properties

Property	Value	Source
Water Solubility	0.00465 mg/mL	ALOGPS
logP	5.97	ALOGPS
logP	4.17	ChemAxon
logS	-5.2	ALOGPS
pKa (Strongest Acidic)	3.5	ChemAxon
pKa (Strongest Basic)	8.4	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	8	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	101.9 Å2	ChemAxon
Rotatable Bond Count	7	ChemAxon
Refractivity	169.16 m3·mol-1	ChemAxon
Polarizability	69.95 Å3	ChemAxon
Number of Rings	6	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	No	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	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

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Details1. ATP-binding cassette sub-family G member 2

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

General Function

Xenobiotic-transporting atpase activity

Specific Function

High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...

Gene Name

ABCG2

Uniprot ID

Q9UNQ0

Uniprot Name

ATP-binding cassette sub-family G member 2

Molecular Weight

72313.47 Da

Details2. Thrombopoietin receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Agonist

General Function

Transmembrane signaling receptor activity

Specific Function

Receptor for thrombopoietin. May represent a regulatory molecule specific for TPO-R-dependent immune responses.

Gene Name

MPL

Uniprot ID

P40238

Uniprot Name

Thrombopoietin receptor

Molecular Weight

71244.08 Da

Details3. Solute carrier family 22 member 8

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

General Function

Sodium-independent organic anion transmembrane transporter activity

Specific Function

Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...

Gene Name

SLC22A8

Uniprot ID

Q8TCC7

Uniprot Name

Solute carrier family 22 member 8

Molecular Weight

59855.585 Da

References

1. SLC22A8 - solute carrier family 22 member 8 (human) [Link]

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Drug created on October 20, 2016 21:09 / Updated on February 21, 2021 18:53