Identification
- Summary
Lusutrombopag is a medication used to treat thrombocytopenia in patients with chronic liver disease scheduled to have a procedure.
- Brand Names
- Mulpleta
- Generic Name
- Lusutrombopag
- DrugBank Accession Number
- DB13125
- Background
Lusutrombopag is an orally bioavailable thrombopoietin receptor (TPOR) agonist developed by Shionogi & Company (Osaka, Japan). TPOR is a regulatory target site for endogenous thrombopoietin, which acts as a primary cytokine to promote megakaryocyte proliferation and differentiation, and affect other hematopoietic lineages as well, including erythroid, granulocytic and lymphoid lineages 5. Thrombocytopenia, which indicates abnormally low levels of platelets, is a common complication related to chronic liver disease. This hematological abnormality, especially in cases of severe thrombocytopenia (platelet count <50,000/μL), creates challenges to patients requiring invasive medical procedures where there is a significant risk for spontaneous bleeding 4. Lusutrombopag binds to the transmembrane domain of TPOR expressed on megakaryocytes, and causes the proliferation and differentiation of megakaryocytic progenitor cells from hematopoietic stem cells Label.
In September 2015, lusutrombopag received its first global approval in Japan to reduce the need for platelet transfusion in adults with chronic liver disease and thrombocytopenia who are schedule to undergo an invasive medical procedure 2. Lusutrombopag was approved by the FDA on July 31st, 2018 for the same therapeutic indication under the market name Mulpleta. In two randomized, double-blind, placebo-controlled trials, patients with chronic liver disease and severe thrombocytopenia who were undergoing an invasive procedure with a platelet count less than 50 x 10^9/L were administered lusutrombopag orally 8. Higher percentages (65-78%) of the patients receiving lusutrombopag required no platelet transfusion prior to the primary invasive procedure compared to those receiving placebo 8. Lusutrombopag is currently in phase III development in various European countries including Austria, Belgium, Germany, and the UK 2.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Lusutrombopag (DB13125)
- Weight
- Average: 591.54
Monoisotopic: 590.1408987 - Chemical Formula
- C29H32Cl2N2O5S
- Synonyms
- Lusutrombopag
- External IDs
- S 888711
- S-888711
Pharmacology
- Indication
Lusutrombopag is indicated for the treatment of thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Chronic thrombocytopenia •••••••••••• ••••• •••••••• •• •••••••• •••••••••• - Contraindications & Blackbox Warnings
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The AUC of lusutrombopag was found to correlate the increased platelet counts. Following administration of 3 mg daily dose in patients with chronic liver disease and thrombocytopenia, the mean (standard deviation) maximum platelet count in patients (N=74) without platelet transfusion was 86.9 (27.2) × 10^9/L, and the median time to reach the maximum platelet count was 12.0 (5 to 35) days Label. Lusutrombopag was not shown to induce any clinically significant QTc prolongation at a dose 8 times the recommended dosage Label.
- Mechanism of action
Lusutrombopag mimics the biological actions of endogenous thrombopoietin (TPO) by acting as an agonist for the thrombopoietin receptor (TPOR) expressed on megakaryocytes. It binds to the transmembrane domain of the receptor and induces thrombocytopoiesis by targeting the same signal transduction system as that of endogenous TPO, which involves the activation of JAK and STAT pathways 6. It stimulates the proliferation and differentiation of bone marrow progenitor cells into megakaryocytes, which undergoes maturation to act as precursor cells for platelets 2. A single megakaryocyte produces and releases thousands of platelets upon maturation and series of remodeling events 7. Lusutrombopag displays high specificity towards human TPORs when compared to murine TPORs 1. Lusutrombopag may affect other hematopoietic lineages as well, including erythroid, granulocytic and lymphoid lineages. One case of increased leukocyte and erythrocyte counts that prolonged for over 120 days was reported following administration in a patient with liver cirrhosis (LC) due to hepatitis C virus 3.
Target Actions Organism AThrombopoietin receptor agonistHumans - Absorption
Lusutrombopag is rapidly absorbed following oral administration 2. It exhibited a dose‐proportional pharmacokinetic profile over the single dose range of 1 mg to 50 mg, which was similar in both healthy subjects and those with chronic liver disease. A geometric mean (%CV) maximal concentration (Cmax) and area under the curve (AUC) in healthy subjects receiving 3 mg of lusutrombopag were 111 (20.4) ng/mL and 2931 (23.4) ng.hr/mL Label. The accumulation ratios of Cmax and AUC were approximately 2 with once‐daily multiple‐dose administration, and steady‐state plasma lusutrombopag concentrations were achieved after Day 5. The time to reach peak plasma concentrations (Tmax) were approximately 6 to 8 hours after oral administration in patients with chronic liver disease Label. Food consumption is not reported to affect the absorption and bioavailability of lusutrombopag Label.
- Volume of distribution
The mean (%CV) lusutrombopag apparent volume of distribution in healthy adult subjects was 39.5 (23.5) L Label.
- Protein binding
The plasma protein binding of lusutrombopag is more than 99.9% Label.
- Metabolism
CYP4 enzymes predominantly contribute to the metabolism of lusutrombopag, especially CYP4A11 Label. Lusutrombopag is reported to mainly undergo ω- and β-oxidation, as well as glucuronidation 2.
- Route of elimination
About 1% of the administered dose of lusutrombopag undergoes urinary excretion. Fecal excretion accounted for 83% of the total dose, where 16% of the dose was excreted as unchanged parent compound 2.
- Half-life
In healthy adult subjects, the terminal elimination half‐life (t1/2) was approximately 27 hours Label.
- Clearance
The approximate mean (%CV) clearance of lusutrombopag in patients with chronic liver disease is estimated to be 1.1 (36.1) L/hr Label.
- Adverse Effects
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There is no known antidote for lusutrombopag: hemodialysis is not expected to enhance the elimination of lusutrombopag from the plasma as there is high protein binding. Overdose may be characterized by excessive platelet counts that may result in thrombotic and thromboembolic complications. In the event of overdose, closely monitor patients and platelet count and treat thrombotic complications in accordance with standard of care Label.
In animal and in vitro studies, lusutrombopag did not display any carcinogenicity, genotoxicity, or reproductive toxicity Label.
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbemaciclib Abemaciclib may decrease the excretion rate of Lusutrombopag which could result in a higher serum level. Abrocitinib The serum concentration of Lusutrombopag can be increased when it is combined with Abrocitinib. Adagrasib The serum concentration of Lusutrombopag can be increased when it is combined with Adagrasib. Afatinib Afatinib may decrease the excretion rate of Lusutrombopag which could result in a higher serum level. Alectinib Alectinib may decrease the excretion rate of Lusutrombopag which could result in a higher serum level. - Food Interactions
- Take with or without food.
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.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Mulpleta Tablet, film coated 3 mg/1 Oral SHIONOGI INC. 2018-08-27 Not applicable US 
Categories
- ATC Codes
- B02BX07 — Lusutrombopag
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as cinnamic acids. These are organic aromatic compounds containing a benzene and a carboxylic acid group forming 3-phenylprop-2-enoic acid.
- Kingdom
- Organic compounds
- Super Class
- Phenylpropanoids and polyketides
- Class
- Cinnamic acids and derivatives
- Sub Class
- Cinnamic acids
- Direct Parent
- Cinnamic acids
- Alternative Parents
- 3-halobenzoic acids and derivatives / Benzamides / Benzylethers / Phenoxy compounds / Anisoles / Methoxybenzenes / Dichlorobenzenes / Benzoyl derivatives / 2,4-disubstituted thiazoles / Alkyl aryl ethers show 12 more
- Substituents
- 1,3-dichlorobenzene / 2,4-disubstituted 1,3-thiazole / 3-halobenzoic acid or derivatives / Alkyl aryl ether / Anisole / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Azole show 32 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 6LL5JFU42F
- CAS number
- 1110766-97-6
- InChI Key
- NOZIJMHMKORZBA-KJCUYJGMSA-N
- InChI
- InChI=1S/C29H32Cl2N2O5S/c1-5-6-7-8-12-38-18(3)20-10-9-11-21(26(20)37-4)25-16-39-29(32-25)33-27(34)19-14-23(30)22(24(31)15-19)13-17(2)28(35)36/h9-11,13-16,18H,5-8,12H2,1-4H3,(H,35,36)(H,32,33,34)/b17-13+/t18-/m0/s1
- IUPAC Name
- (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazol-2-yl)carbamoyl]phenyl}-2-methylprop-2-enoic acid
- SMILES
- CCCCCCO[C@@H](C)C1=C(OC)C(=CC=C1)C1=CSC(NC(=O)C2=CC(Cl)=C(\C=C(/C)C(O)=O)C(Cl)=C2)=N1
References
- General References
- Yoshida H, Yamada H, Nogami W, Dohi K, Kurino-Yamada T, Sugiyama K, Takahashi K, Gahara Y, Kitaura M, Hasegawa M, Oshima I, Kuwabara K: Development of a new knock-in mouse model and evaluation of pharmacological activities of lusutrombopag, a novel, nonpeptidyl small-molecule agonist of the human thrombopoietin receptor c-Mpl. Exp Hematol. 2018 Mar;59:30-39.e2. doi: 10.1016/j.exphem.2017.12.005. Epub 2017 Dec 20. [Article]
- Kim ES: Lusutrombopag: First Global Approval. Drugs. 2016 Jan;76(1):155-8. doi: 10.1007/s40265-015-0525-4. [Article]
- Sakamaki A, Watanabe T, Abe S, Kamimura K, Tsuchiya A, Takamura M, Kawai H, Yamagiwa S, Terai S: Lusutrombopag increases hematocytes in a compensated liver cirrhosis patient. Clin J Gastroenterol. 2017 Jun;10(3):261-264. doi: 10.1007/s12328-017-0735-2. Epub 2017 Mar 21. [Article]
- Sato S, Miyake T, Kataoka M, Isoda K, Yazaki T, Tobita H, Ishimura N, Kinoshita Y: Efficacy of Repeated Lusutrombopag Administration for Thrombocytopenia in a Patient Scheduled for Invasive Hepatocellular Carcinoma Treatment. Intern Med. 2017 Nov 1;56(21):2887-2890. doi: 10.2169/internalmedicine.8791-16. Epub 2017 Sep 25. [Article]
- Ninos JM, Jefferies LC, Cogle CR, Kerr WG: The thrombopoietin receptor, c-Mpl, is a selective surface marker for human hematopoietic stem cells. J Transl Med. 2006 Feb 16;4:9. doi: 10.1186/1479-5876-4-9. [Article]
- Kuter DJ: The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol. 2013 Jul;98(1):10-23. doi: 10.1007/s12185-013-1382-0. Epub 2013 Jul 3. [Article]
- Patel SR, Hartwig JH, Italiano JE Jr: The biogenesis of platelets from megakaryocyte proplatelets. J Clin Invest. 2005 Dec;115(12):3348-54. doi: 10.1172/JCI26891. [Article]
- FDA approves lusutrombopag for thrombocytopenia in adults with chronic liver disease [Link]
- External Links
- PubChem Compound
- 49843517
- PubChem Substance
- 347829248
- ChemSpider
- 28529616
- 2054984
- ChEBI
- 136051
- ChEMBL
- CHEMBL2107831
- ZINC
- ZINC000084759273
- Wikipedia
- Lusutrombopag
- FDA label
- Download (410 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Not Yet Recruiting Treatment Immune Thrombocytopenia (ITP) 1 3 Completed Treatment Chronic Liver Disease / Thrombocytopenia 1 2 Terminated Treatment Immune Thrombocytopenia (ITP) 2 1 Completed Treatment Healthy Volunteers (HV) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 3 MG Tablet, film coated Oral 3 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US7601746 No 2009-10-13 2024-09-05 US US8889722 No 2014-11-18 2028-07-29 US US8530668 No 2013-09-10 2030-01-21 US US9427402 No 2016-08-30 2031-09-29 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Practically insoluble FDA Label - Predicted Properties
Property Value Source Water Solubility 0.000145 mg/mL ALOGPS logP 6.94 ALOGPS logP 8.56 Chemaxon logS -6.6 ALOGPS pKa (Strongest Acidic) 3.02 Chemaxon pKa (Strongest Basic) -1.2 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 97.75 Å2 Chemaxon Rotatable Bond Count 13 Chemaxon Refractivity 157.53 m3·mol-1 Chemaxon Polarizability 63.73 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 0 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
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 231.68979 predictedDeepCCS 1.0 (2019) [M+H]+ 233.62077 predictedDeepCCS 1.0 (2019) [M+Na]+ 239.36159 predictedDeepCCS 1.0 (2019)
Targets
- 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
References
- Yoshida H, Yamada H, Nogami W, Dohi K, Kurino-Yamada T, Sugiyama K, Takahashi K, Gahara Y, Kitaura M, Hasegawa M, Oshima I, Kuwabara K: Development of a new knock-in mouse model and evaluation of pharmacological activities of lusutrombopag, a novel, nonpeptidyl small-molecule agonist of the human thrombopoietin receptor c-Mpl. Exp Hematol. 2018 Mar;59:30-39.e2. doi: 10.1016/j.exphem.2017.12.005. Epub 2017 Dec 20. [Article]
- Kim ES: Lusutrombopag: First Global Approval. Drugs. 2016 Jan;76(1):155-8. doi: 10.1007/s40265-015-0525-4. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Leukotriene-b4 20-monooxygenase activity
- Specific Function
- Catalyzes the omega- and (omega-1)-hydroxylation of various fatty acids such as laurate, myristate and palmitate. Has little activity toward prostaglandins A1 and E1. Oxidizes arachidonic acid to 2...
- Gene Name
- CYP4A11
- Uniprot ID
- Q02928
- Uniprot Name
- Cytochrome P450 4A11
- Molecular Weight
- 59347.31 Da
Transporters
- Kind
- Protein
- Organism
- Humans
- 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
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- 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
Drug created at October 21, 2016 03:27 / Updated at December 04, 2021 06:47