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
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

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

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

TargetActionsOrganism
ATyrosine-protein kinase JAK2
inhibitor
Humans
AReceptor-type tyrosine-protein kinase FLT3
inhibitor
Humans
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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Toxicity

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.
DrugInteraction
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Pacritinib.
AbametapirThe serum concentration of Pacritinib can be increased when it is combined with Abametapir.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Pacritinib.
AcalabrutinibThe serum concentration of Acalabrutinib can be increased when it is combined with Pacritinib.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Pacritinib.
AcetaminophenThe serum concentration of Acetaminophen can be increased when it is combined with Pacritinib.
AcetylcholineThe risk or severity of adverse effects can be increased when Pacritinib is combined with Acetylcholine.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Pacritinib.
AcyclovirThe serum concentration of Acyclovir can be increased when it is combined with Pacritinib.
AdenosineThe risk or severity of QTc prolongation can be increased when Pacritinib is combined with Adenosine.
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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

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
VonjoCapsule100 mg/1OralCTI BioPharma Corp.2022-02-28Not applicableUS flag

Categories

ATC Codes
L01EJ03 — Pacritinib
Drug Categories
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
  1. 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]
  2. FDA Approved Drug Products: Vonjo (pacritinib) capsules for oral use [Link]
  3. National Organization for Rare Disorders: Primary Myelofibrosis [Link]
  4. BioSpace News: CTI BioPharma Announces FDA Accelerated Approval of VONJO™ (pacritinib) for the Treatment of Adult Patients with Myelofibrosis and Thrombocytopenia [Link]
PubChem Compound
46216796
PubChem Substance
347828062
ChemSpider
28518965
BindingDB
50210177
RxNav
2595243
ChEMBL
CHEMBL2035187
ZINC
ZINC000043153645
PDBe Ligand
6T3
Wikipedia
Pacritinib
PDB Entries
5lbz

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentPost Essential Thrombocythaemia Myelofibrosis / Post Polycythemia Vera Myelofibrosis / Primary Myelofibrosis (PMF)1
3TerminatedTreatmentCoronavirus Disease 2019 (COVID‑19) / COVID1
3TerminatedTreatmentPost Essential Thrombocythaemia Myelofibrosis / Post Polycythemia Vera Myelofibrosis / Primary Myelofibrosis (PMF)2
2Active Not RecruitingTreatmentMyelofibrosis1
2CompletedTreatmentIndolent Lymphoma / Lymphoma, Hodgkins / Mantle Cell Lymphoma (MCL)1
2CompletedTreatmentPost Essential Thrombocythaemia Myelofibrosis / Post Polycythemia Vera Myelofibrosis / Primary Myelofibrosis (PMF)1
2Not Yet RecruitingTreatmentDisorders, Lymphoproliferative / T-Cell Neoplasm1
2RecruitingTreatmentProstate Cancer1
2TerminatedPreventionAcute Myeloid Leukemia (AML)1
2TerminatedTreatmentAcute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome / Acute, recurrent Myeloid Leukemia / Chronic Myelomonocytic Leukemia (CMML) / Refractory Acute Lymphoblastic Leukemia (ALL) / Refractory Acute Myeloid Leukemia (AML) / Relapsed Acute Lymphoblastic Leukemia (ALL)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral100 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9573964No2017-02-212028-05-05US flag
US8153632No2012-04-102029-01-17US flag
US8980873No2015-03-172030-03-25US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0381 mg/mLALOGPS
logP4.78ALOGPS
logP4.58Chemaxon
logS-4.1ALOGPS
pKa (Strongest Acidic)14.1Chemaxon
pKa (Strongest Basic)8.86Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count7Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area68.74 Å2Chemaxon
Rotatable Bond Count4Chemaxon
Refractivity139.43 m3·mol-1Chemaxon
Polarizability52.32 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
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

Targets

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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
  1. 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
  1. FDA Approved Drug Products: Vonjo (pacritinib) capsules for oral use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
Inducer
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
  1. FDA Approved Drug Products: Vonjo (pacritinib) capsules for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Inducer
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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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