Identification
- Summary
Pacritinib is a kinase inhibitor used for the treatment of primary and secondary myelofibrosis in adult patients with significantly reduced platelet counts.
- Brand Names
- Vonjo
- Generic Name
- Pacritinib
- DrugBank Accession Number
- DB11697
- Background
Myelofibrosis (MF) is a rare disorder characterized by hematopoietic abnormalities and fibrosis within the bone marrow.3 The underlying cause of primary MF is unknown, but secondary MF can arise in patients with a history of polycythemia vera or essential thrombocythemia.3 While some patients may remain asymptomatic, typical symptoms of MF arise from abnormalities in blood cell production and may therefore include various cytopenias, infections, splenomegaly, and general systemic symptoms such as fever.3 Approximately 50% of patients with primary MF have a mutation of the JAK2 gene, which is also commonly mutated in patients with polycythemia vera or essential thrombocythemia.3 JAK2 signaling is important for hematopoiesis and proper immune functioning,2 and while the precise role it plays in the pathogenesis of MF remains unclear, its clear association with MF has made it a desirable therapeutic target in MF treatment.
Pacritinib is an inhibitor of both wild-type and mutant (V617F) JAK2, as well as FMS-like tyrosine kinase 3 (FLT3), which was granted accelerated approval by the FDA in February 2022 for the treatment of both primary and secondary MF in patients with platelet counts < 50 x 109/L.2 It provides a treatment option for patients who have MF with severe thrombocytopenia, which occurs in approximately one-third of MF patients and carries with it a particularly poor prognosis.4
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Pacritinib (DB11697)
- Weight
- Average: 472.589
Monoisotopic: 472.247440906 - Chemical Formula
- C28H32N4O3
- Synonyms
- Pacritinib
- Pacritinibum
- External IDs
- SB 1518
- SB-1518
- SB1518
Pharmacology
- Indication
Pacritinib is indicated for the treatment of adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 x 109/L.2
This indication is approved under accelerated approval based on spleen volume reduction. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.2
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of High risk primary myelofibrosis (pmf) •••••••••••• ••••• •••••••• ••••• ••• • •••••• ••••••• Treatment of High risk secondary myelofibrosis •••••••••••• ••••• •••••••• ••••• ••• • •••••• ••••••• Treatment of High risk secondary myelofibrosis •••••••••••• ••••• •••••••• ••••• ••• • •••••• ••••••• Treatment of Intermediate risk primary myelofibrosis (pmf) •••••••••••• ••••• •••••••• ••••• ••• • •••••• ••••••• Treatment of Intermediate risk secondary myelofibrosis •••••••••••• ••••• •••••••• ••••• ••• • •••••• ••••••• - Contraindications & Blackbox Warnings
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Pacritinib is administered orally twice daily, with or without food. It should not be used in patients with moderate or severe (Child-Pugh B or C) hepatic impairment, nor in patients with significant renal impairment (eGFR <30 mL/min).2
Patients taking pacritinib may experience a prolonged QTc interval - while no cases of torsades de pointes have been reported in clinical trials, QTc prolongations to >500 msec and/or increases in baseline QTc by >60 msec were observed in some patients during clinical trials.2 A baseline QTc interval should be obtained prior to initiating therapy and regular monitoring (including for risk factors, e.g. hypokalemia) should continue throughout therapy.
- Mechanism of action
While the pathogenesis of myelofibrosis (MF) is still poorly understood, both primary and secondary (i.e. post-polycythemia vera or post-essential thrombocythemia) myelofibrosis have been associated with mutations of JAK2.1 Signaling pathways initiated by JAK2 generate a number of cytokines and growth factors responsible for hematopoiesis and immune functioning, and its dysregulation is thought to be a driver of MF pathogenesis.
Pacritinib is thought to exert its pharmacologic activity via inhibition of wild-type JAK2, mutant JAK2V617F, and FMS-like tyrosine kinase 3 (FLT3).2 It has a greater inhibitory potency towards JAK2 than related proteins (e.g. JAK3, TYK2), and does not inhibit JAK1 at clinically relevant concentrations.2
Pacritinib also exhibits some inhibitory activity against other cellular kinases (e.g. CSF1R and IRAK1), although the clinical significance of this activity is unknown.2
Target Actions Organism ATyrosine-protein kinase JAK2 inhibitorHumans AReceptor-type tyrosine-protein kinase FLT3 inhibitorHumans - Absorption
Following oral administration of 200mg pacritinib twice daily, the mean Cmax and AUC0-12 at steady-state were 8.4 mg/L and 95.6 mg*h/L, respectively.2 The Tmax is approximately 4-5 hours post-dose.2 Co-administration with food does not significantly impact the pharmacokinetics of pacritinib.
- Volume of distribution
The mean apparent volume of distribution of pacritinib at steady-state is 229 L.2
- Protein binding
Pacritinib is 98.8% protein-bound in plasma.2
- Metabolism
Pacritinib metabolism is mediated primarily by CYP3A4.2 While it undergoes extensive metabolism to at least four identified metabolites - M1, M2, M3, and M41 - parent drug is the major circulating component in plasma and is responsible for the pharmacologic activity.2 The two major metabolites, M1 and M2, represent 9.6% and 10.5% of parent drug exposure, respectively.2
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- Route of elimination
Following oral administration of radiolabeled pacritinib, approximately 87% of the radioactivity was recovered in feces and 6% was recovered in urine.2 Unchanged parent drug was not present in the feces and accounted for only 0.12% of the radioactivity excreted in the urine.2
- Half-life
The mean effective half-life of pacritinib is 27.7 hours.2
- Clearance
The mean apparent clearance of pacritinib is 2.09 L/h.2
- Adverse Effects
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Overdosage with pacritinib may lead to gastrointestinal toxicity, myelosuppression, blurred vision, dizziness, worsening performance status, and sepsis.2 There is no known antidote for pacritinib overdose, and hemodialysis is not expected to enhance its elimination.2
- 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 softwareAbametapir The serum concentration of Pacritinib can be increased when it is combined with Abametapir. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Pacritinib. Acalabrutinib The serum concentration of Acalabrutinib can be increased when it is combined with Pacritinib. Acenocoumarol The serum concentration of Acenocoumarol can be increased when it is combined with Pacritinib. Acetaminophen The serum concentration of Acetaminophen can be increased when it is combined with Pacritinib. - Food Interactions
- Avoid grapefruit products. Grapefruit products can inhibit CYP3A4, which is the enzyme primarily responsible for pacritinib metabolism.
- Avoid St. John's Wort. Pacritinib is metabolized primarily by CYP3A4, an enzyme for which St. John's wort is a potent inducer.
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 Vonjo Capsule 100 mg/1 Oral CTI BioPharma Corp. 2022-02-28 Not applicable US 
Categories
- ATC Codes
- L01EJ03 — Pacritinib
- Drug Categories
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- BCRP/ABCG2 Inhibitors
- Cytochrome P-450 CYP1A2 Inducers
- Cytochrome P-450 CYP1A2 Inducers (strength unknown)
- Cytochrome P-450 CYP1A2 Inhibitors
- Cytochrome P-450 CYP1A2 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2C19 Inhibitors
- Cytochrome P-450 CYP2C19 inhibitors (strength unknown)
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inducers
- Cytochrome P-450 CYP3A4 Inducers (strength unknown)
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Janus Kinase 2, antagonists & inhibitors
- Janus Kinase Inhibitor
- Janus Kinases, antagonists & inhibitors
- Kinase Inhibitor
- OCT1 inhibitors
- OCT2 Inhibitors
- P-glycoprotein inhibitors
- Potential QTc-Prolonging Agents
- Protein Kinase Inhibitors
- QTc Prolonging Agents
- Tyrosine Kinase Inhibitors
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as phenol ethers. These are aromatic compounds containing an ether group substituted with a benzene ring.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Phenol ethers
- Sub Class
- Not Available
- Direct Parent
- Phenol ethers
- Alternative Parents
- Alkyl aryl ethers / Pyrimidines and pyrimidine derivatives / N-alkylpyrrolidines / Heteroaromatic compounds / Trialkylamines / Oxacyclic compounds / Dialkyl ethers / Azacyclic compounds / Hydrocarbon derivatives
- Substituents
- Alkyl aryl ether / Amine / Aromatic heteropolycyclic compound / Azacycle / Dialkyl ether / Ether / Heteroaromatic compound / Hydrocarbon derivative / N-alkylpyrrolidine / Organic nitrogen compound
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- G22N65IL3O
- CAS number
- 937272-79-2
- InChI Key
- HWXVIOGONBBTBY-ONEGZZNKSA-N
- InChI
- InChI=1S/C28H32N4O3/c1-2-13-32(12-1)14-17-35-27-9-8-25-19-24(27)21-34-16-4-3-15-33-20-22-6-5-7-23(18-22)26-10-11-29-28(30-25)31-26/h3-11,18-19H,1-2,12-17,20-21H2,(H,29,30,31)/b4-3+
- IUPAC Name
- (16E)-11-[2-(pyrrolidin-1-yl)ethoxy]-14,19-dioxa-5,7,27-triazatetracyclo[19.3.1.1^{2,6}.1^{8,12}]heptacosa-1(25),2(27),3,5,8,10,12(26),16,21,23-decaene
- SMILES
- C(CN1CCCC1)OC1=CC=C2NC3=NC=CC(=N3)C3=CC(COC\C=C\COCC1=C2)=CC=C3
References
- Synthesis Reference
A245943 — William AD, Lee AC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Tan E, Chen D, Williams M, Sun ET, Goh KC, Ong WC, Goh SK, Hart S, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW: Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6). 1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J Med Chem. 2011 Jul 14;54(13):4638-58. doi: 10.1021/jm200326p. Epub 2011 Jun 15.
- General References
- Jayaraman R, Pasha MK, Williams A, Goh KC, Ethirajulu K: Metabolism and Disposition of Pacritinib (SB1518), an Orally Active Janus Kinase 2 Inhibitor in Preclinical Species and Humans. Drug Metab Lett. 2015;9(1):28-47. doi: 10.2174/1872312809666150119105250. [Article]
- FDA Approved Drug Products: Vonjo (pacritinib) capsules for oral use [Link]
- National Organization for Rare Disorders: Primary Myelofibrosis [Link]
- BioSpace News: CTI BioPharma Announces FDA Accelerated Approval of VONJO™ (pacritinib) for the Treatment of Adult Patients with Myelofibrosis and Thrombocytopenia [Link]
- External Links
- PubChem Compound
- 46216796
- PubChem Substance
- 347828062
- ChemSpider
- 28518965
- BindingDB
- 50210177
- 2595243
- ChEMBL
- CHEMBL2035187
- ZINC
- ZINC000043153645
- PDBe Ligand
- 6T3
- Wikipedia
- Pacritinib
- PDB Entries
- 5lbz / 8bpv
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Recruiting Treatment Post Polycythemia Vera Myelofibrosis / Post-essential Thrombocythemia Myelofibrosis (Post-ET MF) / Primary Myelofibrosis (PMF) 1 3 Terminated Treatment Post Polycythemia Vera Myelofibrosis / Post-essential Thrombocythemia Myelofibrosis (Post-ET MF) / Primary Myelofibrosis (PMF) 2 2 Active Not Recruiting Treatment Myelofibrosis 1 2 Active Not Recruiting Treatment Prostate Cancer 1 2 Completed Treatment Hodgkin's Lymphoma / Indolent Lymphoma / Mantle Cell Lymphoma (MCL) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 100 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9573964 No 2017-02-21 2028-05-05 US US8153632 No 2012-04-10 2029-01-17 US US8980873 No 2015-03-17 2030-03-25 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0381 mg/mL ALOGPS logP 4.78 ALOGPS logP 4.58 Chemaxon logS -4.1 ALOGPS pKa (Strongest Acidic) 14.1 Chemaxon pKa (Strongest Basic) 8.86 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 7 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 68.74 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 139.43 m3·mol-1 Chemaxon Polarizability 52.32 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No 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 splash10-00di-0001900000-a0790efadbbe96a747b0 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-00di-0001900000-0fc3fcdee06e54ca1fd8 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-00di-1003900000-54ef811ea05b14c97fb4 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-00di-0009000000-75348a363534c42fe921 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0734-9108100000-825a798629ab60d2c576 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-00di-0009300000-ef4304ca5e1b74d12482 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 205.2678 predictedDeepCCS 1.0 (2019) [M+H]+ 207.62581 predictedDeepCCS 1.0 (2019) [M+Na]+ 214.37361 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Sh2 domain binding
- Specific Function
- Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptiv...
- Gene Name
- JAK2
- Uniprot ID
- O60674
- Uniprot Name
- Tyrosine-protein kinase JAK2
- Molecular Weight
- 130672.475 Da
References
- FDA Approved Drug Products: Vonjo (pacritinib) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Vascular endothelial growth factor-activated receptor activity
- Specific Function
- Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells...
- Gene Name
- FLT3
- Uniprot ID
- P36888
- Uniprot Name
- Receptor-type tyrosine-protein kinase FLT3
- Molecular Weight
- 112902.51 Da
References
- FDA Approved Drug Products: Vonjo (pacritinib) capsules for oral use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitorInducer
- General Function
- Vitamin d3 25-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 performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- FDA Approved Drug Products: Vonjo (pacritinib) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- InhibitorInducer
- 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
- FDA Approved Drug Products: Vonjo (pacritinib) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55930.545 Da
References
- FDA Approved Drug Products: Vonjo (pacritinib) capsules for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- 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
References
- FDA Approved Drug Products: Vonjo (pacritinib) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- 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
References
- FDA Approved Drug Products: Vonjo (pacritinib) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Secondary active organic cation transmembrane transporter activity
- Specific Function
- Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnico...
- Gene Name
- SLC22A1
- Uniprot ID
- O15245
- Uniprot Name
- Solute carrier family 22 member 1
- Molecular Weight
- 61153.345 Da
References
- FDA Approved Drug Products: Vonjo (pacritinib) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Quaternary ammonium group transmembrane transporter activity
- Specific Function
- Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creat...
- Gene Name
- SLC22A2
- Uniprot ID
- O15244
- Uniprot Name
- Solute carrier family 22 member 2
- Molecular Weight
- 62579.99 Da
References
- FDA Approved Drug Products: Vonjo (pacritinib) capsules for oral use [Link]
Drug created at October 20, 2016 20:40 / Updated at September 02, 2022 17:58