Identification
- Summary
Anagrelide is a platelet-reducing agent used to treat thrombocythemia, and its related complications, secondary to myeloproliferative neoplasms.
- Brand Names
- Agrylin, Xagrid
- Generic Name
- Anagrelide
- DrugBank Accession Number
- DB00261
- Background
Anagrelide is a platelet-reducing agent used to lower dangerously elevated platelet levels (i.e. to treat thrombocythemia) in patients with myeloproliferative neoplasms.9 It is an oral imidazoquinazoline that was first approved for use in the US in 1997.8 It appears to carry a better response rate than other thrombocythemia treatments (e.g. busulfan, hydroxyurea) and may be better tolerated.8
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Anagrelide (DB00261)
- Weight
- Average: 256.088
Monoisotopic: 254.996617275 - Chemical Formula
- C10H7Cl2N3O
- Synonyms
- Anagrelida
- Anagrelide
- Anagrelidum
- External IDs
- BL-4162A
Pharmacology
- Indication
Anagrelide is indicated for the treatment of thrombocythemia, secondary to malignant neoplasms, to reduce platelet count and the associated risk of thrombosis. It is also beneficial in the amelioration of thrombocythemia symptoms including thrombo-hemorrhagic events.9
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Thrombocythemia •••••••••••• ••••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Anagrelide decreases platelet counts by suppressing transcription factors necessary for the synthesis and maturation of platelet-producing cells.9 The drug itself appears to have a relatively short residence time in the body necessitating twice or four times daily dosing. However, given that the pharmacological effect of anagrelide therapy is reliant on a gradual suppression of platelet-producing cells, it may take 7 to 14 days11 for its administration to be reflected in reduced platelet counts - for this reason any changes to anagrelide doses should not exceed 0.5 mg/day in any one week.9
Evidence from animal studies suggests anagrelide may impair female fertility.9 Female patients of reproductive age should be advised of the potential for adverse effects on fertility prior to initiating therapy.
- Mechanism of action
The exact mechanism by which anagrelide lowers platelet count is unclear. Evidence from human trials suggests a dose-related suppression of megakaryocyte maturation, the cells responsible for platelet production - blood drawn from patients receiving anagrelide showed a disruption to the post-mitotic phase of megakaryocyte development and a subsequent reduction in their size and ploidy.11 This may be achieved via indirect suppression of certain transcription factors required for megakaryocytopoeisis, including GATA-1 and FOG-1.9
Anagrelide is a known inhibitor of phosphodiesterase 3A (PDE3A), although its platelet-lowering effects appear unrelated to this inhibition.6 While PDE3 inhibitors, as a class, can inhibit platelet aggregation, this effect is only seen at higher anagrelide doses (i.e. greater than those required to reduce platelet count).9 Modulation of PDE3A has been implicated in causing cell cycle arrest and apoptosis in cancer cells expressing both PDE3A and SLFN12,4 and may be of value in the treatment of gastrointestinal stromal tumours.5
Target Actions Organism AcGMP-inhibited 3',5'-cyclic phosphodiesterase A inhibitorHumans - Absorption
Following oral administration, the bioavailability of anagrelide is approximately 70%.9 Given on an empty stomach, the Cmax is reached within 1 hour (Tmax) of administration. Co-administration with food slightly lowers the Cmax and increases the AUC, but not to a clinically significant extent.9
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
Anagrelide is extensively metabolized, primarily in the liver by cytochrome P450 1A2 (CYP1A2), into two major metabolites: 6,7-dichloro-3-hydroxy-1,5 dihydro-imidazo[2,1-b]quinazolin-2-one (3-hydroxy anagrelide) and 2-amino-5,6-dichloro-3,4,-dihydroquinazoline (RL603). The 3-hydroxy metabolite is considered pharmacologically active and carries a similar potency and efficacy in regards to its platelet-lowering effects, but inhibits PDE3 with a potency 40x greater than that of the parent drug.9
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- Route of elimination
Following metabolism, urinary excretion of metabolites appears to be the primary means of anagrelide elimination. Less than 1% of an administered dose is recovered in the urine as unchanged parent drug, while approximately 3% and 16-20% of the administered dose is recovered as 3-hydroxy anagrelide and RL603, respectively.9
- Half-life
The t1/2 of anagrelide and its active metabolite, 3-hydroxy anagrelide, are approximately 1.5 hours and 2.5 hours, respectively.9
- Clearance
Not Available
- Adverse Effects
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The oral LD50 of anagrelide as reported in rats and mice is >1500mg/kg and >2500mg/kg, respectively.10 Symptoms of overdose may include hypotension, sinus tachycardia, and vomiting. As the therapeutic effect of anagrelide (i.e. platelet reduction) is dose-related, significant thrombocytopenia is expected in instances of overdose.9 Treatment of overdose should involve careful monitoring of platelet counts and complications such as bleeding.9 Employ symptomatic and supportive measures if clinically indicated.
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Anagrelide can be increased when it is combined with Abametapir. Abatacept The metabolism of Anagrelide can be increased when combined with Abatacept. Abciximab The risk or severity of bleeding can be increased when Anagrelide is combined with Abciximab. Abiraterone The serum concentration of Anagrelide can be increased when it is combined with Abiraterone. Abrocitinib The risk or severity of bleeding and thrombocytopenia can be increased when Anagrelide is combined with Abrocitinib. - Food Interactions
- Take with or without food. Co-administration with food slightly alters pharmacokinetics, but not to a clinically significant extent.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Anagrelide hydrochloride VNS4435G39 58579-51-4 TVWRQCIPWUCNMI-UHFFFAOYSA-N Anagrelide hydrochloride monohydrate YTM763Y5C8 823178-43-4 YLFXXKJQBOJJIX-UHFFFAOYSA-N - Product Images
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Agrylin Capsule 0.5 mg Oral Takeda 1998-01-06 Not applicable Canada 
Agrylin Capsule 0.5 mg/1 Oral Takeda Pharmaceuticals America, Inc. 1997-03-14 Not applicable US 
Agrylin Capsule 1 mg/1 Oral Shire 1997-03-14 2008-03-31 US Anagrelide Mylan Capsule 0.5 mg Oral Mylan Pharmaceuticals Limited 2021-01-27 Not applicable EU 
Anagrelide Mylan Capsule 1 mg Oral Mylan Pharmaceuticals Limited 2021-01-27 Not applicable EU - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Anagrelide Capsule 0.5 mg/1 Oral Torrent Pharmaceuticals Limited 2017-06-30 Not applicable US Anagrelide Capsule 1 mg/1 Oral Torrent Pharmaceuticals Limited 2017-06-30 Not applicable US Anagrelide Hydrochloride Capsule 0.5 mg/1 Oral Mylan Pharmaceuticals 2011-02-28 2014-01-31 US Anagrelide Hydrochloride Capsule 0.5 mg/1 Oral Eon Labs, Inc. 2005-04-18 2012-03-31 US Anagrelide Hydrochloride Capsule 0.5 mg/1 Oral Teva Pharmaceuticals USA, Inc. 2005-04-18 Not applicable US 
Categories
- ATC Codes
- L01XX35 — Anagrelide
- Drug Categories
- Agents producing tachycardia
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Antiplatelet agents
- Cardiovascular Agents
- Cytochrome P-450 CYP1A2 Inhibitors
- Cytochrome P-450 CYP1A2 Inhibitors (weak)
- Cytochrome P-450 CYP1A2 Substrates
- Cytochrome P-450 CYP1A2 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Decreased Platelet Production
- Hematologic Agents
- Heterocyclic Compounds, Fused-Ring
- Highest Risk QTc-Prolonging Agents
- Narrow Therapeutic Index Drugs
- Phosphodiesterase 3 Inhibitors
- Phosphodiesterase Inhibitors
- Platelet-reducing Agents
- QTc Prolonging Agents
- Thrombocytosis
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as quinazolines. These are compounds containing a quinazoline moiety, which is made up of two fused six-member aromatic rings, a benzene ring and a pyrimidine ring.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Diazanaphthalenes
- Sub Class
- Benzodiazines
- Direct Parent
- Quinazolines
- Alternative Parents
- Benzenoids / Aryl chlorides / Imidazolines / Propargyl-type 1,3-dipolar organic compounds / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds / Organochlorides / Hydrocarbon derivatives
- Substituents
- 3-imidazoline / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Hydrocarbon derivative / Organic 1,3-dipolar compound / Organic nitrogen compound / Organic oxygen compound
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- imidazoquinazoline (CHEBI:142290)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- K9X45X0051
- CAS number
- 68475-42-3
- InChI Key
- OTBXOEAOVRKTNQ-UHFFFAOYSA-N
- InChI
- InChI=1S/C10H7Cl2N3O/c11-6-1-2-7-5(9(6)12)3-15-4-8(16)14-10(15)13-7/h1-2H,3-4H2,(H,13,14,16)
- IUPAC Name
- 6,7-dichloro-1H,2H,3H,5H-imidazo[2,1-b]quinazolin-2-one
- SMILES
- ClC1=CC=C2N=C3NC(=O)CN3CC2=C1Cl
References
- Synthesis Reference
Warren Neil Beverung, Jr., Anthony Partyka, "Optionally substituted 1,2,3,5-tetrahydroimidezo(2,1-b)-quinazolin-2-ones and 6(H)-1,2,3,4-tetrahydropyimido(2,1-b)quinazolin-2-ones." U.S. Patent US3932407A, issued January 1976.
US3932407- General References
- Voglova J, Maisnar V, Beranek M, Chrobak L: [Combination of imatinib and anagrelide in treatment of chronic myeloid leukemia in blastic phase]. Vnitr Lek. 2006 Sep;52(9):819-22. [Article]
- Petrides PE: Anagrelide: what was new in 2004 and 2005? Semin Thromb Hemost. 2006 Jun;32(4 Pt 2):399-408. [Article]
- Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D, Wilkins BS, van der Walt JD, Reilly JT, Grigg AP, Revell P, Woodcock BE, Green AR: Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005 Jul 7;353(1):33-45. [Article]
- An R, Liu J, He J, Wang F, Zhang Q, Yu Q: PDE3A inhibitor anagrelide activates death signaling pathway genes and synergizes with cell death-inducing cytokines to selectively inhibit cancer cell growth. Am J Cancer Res. 2019 Sep 1;9(9):1905-1921. eCollection 2019. [Article]
- Pulkka OP, Gebreyohannes YK, Wozniak A, Mpindi JP, Tynninen O, Icay K, Cervera A, Keskitalo S, Murumagi A, Kulesskiy E, Laaksonen M, Wennerberg K, Varjosalo M, Laakkonen P, Lehtonen R, Hautaniemi S, Kallioniemi O, Schoffski P, Sihto H, Joensuu H: Anagrelide for Gastrointestinal Stromal Tumor. Clin Cancer Res. 2019 Mar 1;25(5):1676-1687. doi: 10.1158/1078-0432.CCR-18-0815. Epub 2018 Dec 7. [Article]
- Espasandin YR, Glembotsky AC, Grodzielski M, Lev PR, Goette NP, Molinas FC, Marta RF, Heller PG: Anagrelide platelet-lowering effect is due to inhibition of both megakaryocyte maturation and proplatelet formation: insight into potential mechanisms. J Thromb Haemost. 2015 Apr;13(4):631-42. doi: 10.1111/jth.12850. Epub 2015 Feb 18. [Article]
- Gisslinger H, Buxhofer-Ausch V, Hodisch J, Radinoff A, Karyagina E, Kyrcz-Krzemien S, Abdulkadyrov K, Gerbutavicius R, Melikyan A, Burgstaller S, Hus M, Kloczko J, Yablokova V, Tzvetkov N, Calbecka M, Shneyder T, Warzocha K, Jurgutis M, Kaplanov K, Jilma B, Schoergenhofer C, Klade C: A phase III randomized, multicentre, double blind, active controlled trial to compare the efficacy and safety of two different anagrelide formulations in patients with essential thrombocythaemia - the TEAM-ET 2.0 trial. Br J Haematol. 2019 May;185(4):691-700. doi: 10.1111/bjh.15824. Epub 2019 Mar 28. [Article]
- Mazzucconi MG, Redi R, Bernasconi S, Bizzoni L, Dragoni F, Latagliata R, Santoro C, Mandelli F: A long-term study of young patients with essential thrombocythemia treated with anagrelide. Haematologica. 2004 Nov;89(11):1306-13. [Article]
- FDA Approved Drug Products: Agrylin (anagrelide) oral capsules [Link]
- CaymanChem: Anagrelide MSDS [Link]
- Health Canada Product Monograph: Agrylin (anagrelide hydrochloride) capsules for oral use [Link]
- External Links
- Human Metabolome Database
- HMDB0014406
- KEGG Drug
- D07455
- PubChem Compound
- 2182
- PubChem Substance
- 46508863
- ChemSpider
- 2097
- BindingDB
- 50000334
- 596724
- ChEBI
- 142290
- ChEMBL
- CHEMBL760
- ZINC
- ZINC000003871541
- Therapeutic Targets Database
- DAP000612
- PharmGKB
- PA164742986
- PDBe Ligand
- J33
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Anagrelide
- PDB Entries
- 7eg0
- FDA label
- Download (295 KB)
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 4 Completed Treatment Thrombocythemia, Hemorrhagic 1 3 Active Not Recruiting Treatment Essential Thrombocythemia (ET) 1 3 Completed Not Available Essential Thrombocythemia (ET) 1 3 Completed Prevention Essential Thrombocythemia (ET) 1 3 Completed Treatment Essential Thrombocythemia (ET) 3
Pharmacoeconomics
- Manufacturers
- Shire development inc
- Alphapharm pty ltd
- Barr laboratories inc
- Impax laboratories inc
- Ivax pharmaceuticals inc sub teva pharmaceuticals usa
- Mylan laboratories inc
- Roxane laboratories inc
- Sandoz inc
- Watson laboratories
- Packagers
- Alphapharm Party Ltd.
- Barr Pharmaceuticals
- Cipla Ltd.
- D.M. Graham Laboratories Inc.
- Eon Labs
- Genpharm LP
- Global Pharmaceuticals
- Impax Laboratories Inc.
- Ivax Pharmaceuticals
- Mallinckrodt Inc.
- Murfreesboro Pharmaceutical Nursing Supply
- Mylan
- Physicians Total Care Inc.
- Resource Optimization and Innovation LLC
- Shire Inc.
- Dosage Forms
Form Route Strength Capsule Oral 1 mg/1 Capsule Oral 0.61 mg Capsule Oral 1 MG Tablet Oral 0.5 mg Tablet Oral 0.75 mg Tablet Oral 1 mg Capsule Oral Capsule Oral 0.5 mg/1 Capsule, coated Oral 0.5 mg Tablet Oral Capsule Oral 0.57 MG Capsule Oral 0.5 mg - Prices
Unit description Cost Unit Agrylin 1 mg capsule 13.03USD each Anagrelide hcl 1 mg capsule 11.91USD each Agrylin 0.5 mg capsule 7.37USD each Anagrelide hcl 0.5 mg capsule 5.94USD each DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Very slightly soluble Not Available logP 2.4 Not Available - Predicted Properties
Property Value Source Water Solubility 0.279 mg/mL ALOGPS logP 1.95 ALOGPS logP 1.94 Chemaxon logS -3 ALOGPS pKa (Strongest Acidic) 11.25 Chemaxon pKa (Strongest Basic) 3.62 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 44.7 Å2 Chemaxon Rotatable Bond Count 0 Chemaxon Refractivity 63.25 m3·mol-1 Chemaxon Polarizability 23.61 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9972 Blood Brain Barrier + 0.848 Caco-2 permeable + 0.5826 P-glycoprotein substrate Substrate 0.7133 P-glycoprotein inhibitor I Non-inhibitor 0.5302 P-glycoprotein inhibitor II Non-inhibitor 0.8438 Renal organic cation transporter Inhibitor 0.7044 CYP450 2C9 substrate Non-substrate 0.8171 CYP450 2D6 substrate Non-substrate 0.7564 CYP450 3A4 substrate Substrate 0.725 CYP450 1A2 substrate Inhibitor 0.688 CYP450 2C9 inhibitor Non-inhibitor 0.7769 CYP450 2D6 inhibitor Non-inhibitor 0.736 CYP450 2C19 inhibitor Non-inhibitor 0.6425 CYP450 3A4 inhibitor Non-inhibitor 0.5974 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6563 Ames test Non AMES toxic 0.6107 Carcinogenicity Non-carcinogens 0.8902 Biodegradation Not ready biodegradable 1.0 Rat acute toxicity 2.8127 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.8386 hERG inhibition (predictor II) Non-inhibitor 0.8405
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 142.7431745 predictedDarkChem Lite v0.1.0 [M-H]- 147.54411 predictedDeepCCS 1.0 (2019) [M+H]+ 143.0150745 predictedDarkChem Lite v0.1.0 [M+H]+ 149.90211 predictedDeepCCS 1.0 (2019) [M+Na]+ 143.2633745 predictedDarkChem Lite v0.1.0 [M+Na]+ 156.05717 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Metal ion binding
- Specific Function
- Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.
- Gene Name
- PDE3A
- Uniprot ID
- Q14432
- Uniprot Name
- cGMP-inhibited 3',5'-cyclic phosphodiesterase A
- Molecular Weight
- 124978.06 Da
References
- Venuti MC, Stephenson RA, Alvarez R, Bruno JJ, Strosberg AM: Inhibitors of cyclic AMP phosphodiesterase. 3. Synthesis and biological evaluation of pyrido and imidazolyl analogues of 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline. J Med Chem. 1988 Nov;31(11):2136-45. [Article]
- An R, Liu J, He J, Wang F, Zhang Q, Yu Q: PDE3A inhibitor anagrelide activates death signaling pathway genes and synergizes with cell death-inducing cytokines to selectively inhibit cancer cell growth. Am J Cancer Res. 2019 Sep 1;9(9):1905-1921. eCollection 2019. [Article]
- FDA Approved Drug Products: Agrylin (anagrelide) oral capsules [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
- 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
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58293.76 Da
References
- Martinez-Selles M, Datino T, Figueiras-Graillet L, Gama JG, Jones C, Franklin R, Fernandez-Aviles F: Cardiovascular safety of anagrelide in healthy subjects: effects of caffeine and food intake on pharmacokinetics and adverse reactions. Clin Drug Investig. 2013 Jan;33(1):45-54. doi: 10.1007/s40261-012-0032-2. [Article]
- FDA Approved Drug Products: Agrylin (anagrelide) oral capsules [Link]
Drug created at June 13, 2005 13:24 / Updated at February 20, 2024 23:54