Identification

Name
Avatrombopag
Accession Number
DB11995
Type
Small Molecule
Groups
Approved, Investigational
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].

Structure
Thumb
Synonyms
Not Available
External IDs
E5501 / YM-477
Product Ingredients
IngredientUNIICASInChI Key
Avatrombopag maleateGDW7M2P1IS677007-74-8MISPBGHDNZYFNM-BTJKTKAUSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DopteletTablet, film coated20 mg/1OralAkaRx, Inc.2018-05-23Not applicableUs
Categories
UNII
3H8GSZ4SQL
CAS number
570406-98-3
Weight
Average: 649.65
Monoisotopic: 648.1510867
Chemical Formula
C29H34Cl2N6O3S2
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

Pharmacology

Indication

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

Associated Conditions
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].

TargetActionsOrganism
UATP-binding cassette sub-family G member 2
inhibitor
Human
AThrombopoietin receptor
agonist
Human
USolute carrier family 22 member 8
inhibitor
Human
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].

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
DrugInteraction
AbirateroneThe metabolism of Avatrombopag can be decreased when combined with Abiraterone.
AcetaminophenThe serum concentration of Avatrombopag can be increased when it is combined with Acetaminophen.
Acetyl sulfisoxazoleThe metabolism of Avatrombopag can be decreased when combined with Acetyl sulfisoxazole.
AcyclovirThe excretion of Acyclovir can be decreased when combined with Avatrombopag.
AlbendazoleThe serum concentration of Avatrombopag can be increased when it is combined with Albendazole.
AllopurinolThe excretion of Allopurinol can be decreased when combined with Avatrombopag.
AlprostadilThe excretion of Alprostadil can be decreased when combined with Avatrombopag.
AmiodaroneThe serum concentration of Avatrombopag can be increased when it is combined with Amiodarone.
AmlodipineThe serum concentration of Avatrombopag can be increased when it is combined with Amlodipine.
AmoxapineThe serum concentration of Avatrombopag can be increased when it is combined with Amoxapine.
Food Interactions
Not Available

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
ChEMBL
CHEMBL2103883
Wikipedia
Avatrombopag
FDA label
Download (436 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Participants1
1CompletedTreatmentHealthy Volunteers3
1CompletedTreatmentIdiopathic Thrombocytopenia Purpura1
1CompletedTreatmentIdiopathic Thrombocytopenic Purpura (ITP)1
1CompletedTreatmentThrombocytopenias1
2CompletedTreatmentChronic Idiopathic Thrombocytopenic Purpura / Purpura, Thrombocytopenic, Idiopathic1
2CompletedTreatmentIdiopathic Thrombocytopenic Purpura (ITP)1
2CompletedTreatmentThrombocytopenia Associated With Chronic Liver Disease1
2CompletedTreatmentThrombocytopenia Related to Chronic Liver Disease1
2CompletedTreatmentThrombocytopenias1
3CompletedTreatmentChronic immune thrombocytopenia / Immune Thrombocytopenia1
3CompletedTreatmentThrombocytopenia Associated With Liver Disease2
3RecruitingSupportive CareChemotherapy-Induced Thrombocytopenia1
3RecruitingTreatmentThrombocytopenias1
3TerminatedTreatmentIdiopathic Thrombocytopenic Purpura (ITP)1
Not AvailableRecruitingNot AvailableThrombocytopenias1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral20 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8765764No2003-01-152023-01-15Us
US7638536No2005-05-052025-05-05Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityInsoluble https://medkoo.com/products/5199
Predicted Properties
PropertyValueSource
Water Solubility0.00465 mg/mLALOGPS
logP5.97ALOGPS
logP4.17ChemAxon
logS-5.2ALOGPS
pKa (Strongest Acidic)3.5ChemAxon
pKa (Strongest Basic)8.4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area101.9 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity169.16 m3·mol-1ChemAxon
Polarizability69.95 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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 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
show 12 more
Substituents
N-arylpiperazine / Nicotinamide / Piperidinecarboxylic acid / Pyridine carboxylic acid or derivatives / 2,4,5-trisubstituted 1,3-thiazole / Dialkylarylamine / Cyclohexylamine / N-alkylpiperazine / Aminopyridine / Aryl halide
show 30 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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
Kind
Protein
Organism
Human
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
Kind
Protein
Organism
Human
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]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
Curator comments
This enzyme action is based on in vitro data.
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Nomoto M, Ferry J, Hussein Z: Population Pharmacokinetic/Pharmacodynamic Analyses of Avatrombopag in Patients With Chronic Liver Disease and Optimal Dose Adjustment Guide With Concomitantly Administered CYP3A and CYP2C9 Inhibitors. J Clin Pharmacol. 2018 Jun 15. doi: 10.1002/jcph.1267. [PubMed:29905956]
  2. Avatrombopag FDA label [File]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da

Drug created on October 20, 2016 15:09 / Updated on October 12, 2018 18:05