Identification

Name
Lusutrombopag
Accession Number
DB13125
Type
Small Molecule
Groups
Approved, Investigational
Description

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].

Structure
Thumb
Synonyms
Not Available
External IDs
S 888711 / S-888711
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MulpletaTablet, film coated3 mg/1OralSHIONOGI INC.2018-08-27Not applicableUs
International/Other Brands
Mulpleta
Categories
UNII
6LL5JFU42F
CAS number
1110766-97-6
Weight
Average: 591.54
Monoisotopic: 590.1408987
Chemical Formula
C29H32Cl2N2O5S
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

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.

Associated Conditions
Pharmacodynamics

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].

TargetActionsOrganism
AThrombopoietin receptor
agonist
Human
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].

Toxicity

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].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbemaciclibThe serum concentration of Lusutrombopag can be increased when it is combined with Abemaciclib.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Lusutrombopag.
AcetaminophenThe serum concentration of Lusutrombopag can be increased when it is combined with Acetaminophen.
Acetylsalicylic acidThe serum concentration of Acetylsalicylic acid can be increased when it is combined with Lusutrombopag.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Lusutrombopag.
AlbendazoleThe serum concentration of Lusutrombopag can be increased when it is combined with Albendazole.
AldosteroneThe serum concentration of Aldosterone can be increased when it is combined with Lusutrombopag.
AlectinibThe serum concentration of Lusutrombopag can be increased when it is combined with Alectinib.
AlitretinoinThe serum concentration of Alitretinoin can be increased when it is combined with Lusutrombopag.
AmbrisentanThe serum concentration of Ambrisentan can be increased when it is combined with Lusutrombopag.
Food Interactions
Not Available

References

General References
  1. 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. [PubMed:29274361]
  2. Kim ES: Lusutrombopag: First Global Approval. Drugs. 2016 Jan;76(1):155-8. doi: 10.1007/s40265-015-0525-4. [PubMed:26666417]
  3. 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. [PubMed:28324272]
  4. 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. [PubMed:28943563]
  5. 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. [PubMed:16480521]
  6. 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. [PubMed:23821332]
  7. 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. [PubMed:16322779]
  8. FDA approves lusutrombopag for thrombocytopenia in adults with chronic liver disease [Link]
External Links
PubChem Compound
49843517
PubChem Substance
347829248
ChemSpider
28529616
ChEBI
136051
ChEMBL
CHEMBL2107831
Wikipedia
Lusutrombopag
FDA label
Download (410 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentImmune Thrombocytopenia1
2TerminatedTreatmentImmune Thrombocytopenia (ITP)1
3CompletedTreatmentChronic Liver Diseases (CLD) / Thrombocytopenias1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral3 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7601746No2004-09-052024-09-05Us
US8889722No2008-07-292028-07-29Us
US8530668No2010-01-212030-01-21Us
US9427402No2011-09-292031-09-29Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityPractically insolubleFDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.000145 mg/mLALOGPS
logP6.94ALOGPS
logP8.56ChemAxon
logS-6.6ALOGPS
pKa (Strongest Acidic)3.02ChemAxon
pKa (Strongest Basic)-1.2ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area97.75 Å2ChemAxon
Rotatable Bond Count13ChemAxon
Refractivity157.53 m3·mol-1ChemAxon
Polarizability63.73 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
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 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
Cinnamic acid / 3-halobenzoic acid or derivatives / Halobenzoic acid or derivatives / Benzamide / Benzoic acid or derivatives / Benzylether / Anisole / Phenoxy compound / Benzoyl / 1,3-dichlorobenzene
show 32 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

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
References
  1. 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. [PubMed:29274361]
  2. Kim ES: Lusutrombopag: First Global Approval. Drugs. 2016 Jan;76(1):155-8. doi: 10.1007/s40265-015-0525-4. [PubMed:26666417]

Enzymes

Kind
Protein
Organism
Human
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
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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
Human
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 on October 20, 2016 21:27 / Updated on November 02, 2018 07:34