NAV

Mavorixafor

This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

Identification

Summary

Mavorixafor is a CXC chemokine receptor 4 antagonist used to treat WHIM syndrome.

Generic Name
Mavorixafor
DrugBank Accession Number
DB05501
Background

Mavorixafor is a CXC chemokine receptor 4 (CXCR4) antagonist.6 It was first approved by the FDA on April 30, 2024, for the treatment of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a genetic immunodeficiency disorder characterized by a reduced number of mature neutrophils and lymphocytes.7 WHIM syndrome is caused by mutations in the CXCR4 gene, which leads to overactivation of CXCR4 signalling pathways.5 Mavorixafor prevents the activation of CXCR4.6

As CXCR4 mutations have also been implicated in human immunodeficiency virus (HIV), Waldenstrom’s macroglobulinemia (WM), B-cell non-Hodgkin lymphoma, and solid tumours, including melanoma, mavorixafor is being investigated in these conditions.3,2

Type
Small Molecule
Groups
Investigational
Structure
3D
Similar Structures
Weight
Average: 349.482
Monoisotopic: 349.226645889
Chemical Formula
C21H27N5
Synonyms
  • 1,4-BUTANEDIAMINE, N-(1H-BENZIMIDAZOL-2-YLMETHYL)-N-((8S)-5,6,7,8-TETRAHYDRO-8-QUINOLINYL)-
  • 1,4-BUTANEDIAMINE, N1-(1H-BENZIMIDAZOL-2-YLMETHYL)-N1-((8S)-5,6,7,8-TETRAHYDRO-8-QUINOLINYL)-
  • CXCR4 INHIBITOR X4P-001
  • N1-(1H-BENZIMIDAZOL-2-YLMETHYL)-N1-((S)-5,6,7,8-TETRAHYDROQUINOLIN-8-YL)-BUTANE-1,4-DIAMINE
External IDs
  • AMD-070
  • AMD-11070
  • AMD070
  • AMD11070
  • X 4P-001
  • X4P 001
  • X4P-001
  • X4P001
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Pharmacology

Indication

Mavorixafor is indicated in patients 12 years of age and older with WHIM syndrome (warts, hypogammaglobulinemia, infections and myelokathexis) to increase the number of circulating mature neutrophils and lymphocytes.6

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofWhim syndrome•••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Mavorixafor works to reduce the symptoms of WHIM syndrome, such as infections and warts, by increasing the mobilization and trafficking of white blood cells from the bone marrow.4 Mavorixafor dose-dependently increases absolute neutrophil count and absolute lymphocyte count.4,6

In healthy volunteers, mavorixafor was shown to prolong the QT interval in a concentration-dependent manner.6

Mechanism of action

WHIM syndrome is a rare primary immunodeficiency disorder predominantly linked to heterozygous gain-of-function mutations in the C-terminus of the C-X-C chemokine receptor 4 (CXCR4), which is a chemokine receptor that regulates immune cell trafficking and homeostasis.4,5,2 CXCR4 is a G protein-coupled receptor (GPCR) that activates downstream pathways such as G-protein signalling, calcium mobilization, and ERK/AKT activation.3 CXC Chemokine Ligand 12 (CXCL12), previously known as stromal-derived factor-1α (SDF-1α), is a sole ligand of CXCR4 2 that binds to the receptor and promotes the trafficking and homing of leukocytes to and from the bone marrow compartment.6 Gain-of-function mutations in the CXCR4 receptor gene result in desensitization defects and increased responsiveness to CXCL12, overactivation of CXCR4 downstream pathways, and the retention of leukocytes in the bone marrow.5,7 Due to a reduced number of mature neutrophils and lymphocytes, patients with WHIM syndrome experience a variety of manifestations of the disorder,7 including panleukopenia and an increased susceptibility to infections and malignancy.5

Mavorixafor is an orally bioavailable CXCR4 antagonist that blocks the binding of CXCL12 to CXCR4. Mavorixafor inhibits the response to CXCL12 in both wild-type and mutated CXCR4 variants associated with WHIM syndrome.6 Treatment with mavorixafor results in increased mobilization of neutrophils and lymphocytes from the bone marrow into the peripheral circulation.6

TargetActionsOrganism
UC-X-C chemokine receptor type 4
antagonist
inhibitor
Humans
Absorption

In adults with WHIM syndrome, the mean (CV%) Cmax at steady-state is 3304 (58.6%) ng/mL and the AUC from 0 to 24 hours (AUC0-24h) is 13970 (58.4%) ngxh/mL following 400 mg once daily.6

Mavorixafor demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in Cmax and AUC0-24h over a dose range of 50 mg (0.125 times the recommended dosage) to 400 mg. Mavorixafor steady-state is reached after approximately 9 to 12 days at the highest approved recommended dosage in healthy subjects. Mavorixafor median (range) Tmax is 2.8 hours (1.9 to 4 hours) at the highest approved recommended dosage. Food decreases Cmax and AUC.6

Volume of distribution

Mavorixafor volume of distribution was 768 L in adults with WHIM syndrome.6

Protein binding

In vitro, mavorixafor is >93% bound to human plasma proteins.6

Metabolism

Mavorixafor is metabolized by CYP3A4 and, to a lesser extent, CYP2D6.6

Route of elimination

After a single oral dose of radiolabeled mavorixafor, 74.2% of the administered dose was recovered out of which 61.0% of administered radioactivity was recovered in feces and 13.2% (3% unchanged) was recovered in the urine over the 240-hour collection period in healthy subjects.6

Half-life

The mean (CV%) terminal half-life was 82 h (34%) following a single-dose administration of mavorixafor 400 mg in healthy subjects.6

Clearance

The mean (CV%) apparent clearance was 62 L/h (40%) following a single-dose administration of mavorixafor 400 mg in healthy subjects. Mavorixafor exhibits at least partial nonlinear apparent clearance; however, this is not clinically significant at the approved recommended dosage.6

Adverse Effects
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Toxicity

There is no information available regarding the LD50 and overdose of mavorixafor.

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.
Not Available
Food Interactions
  • Take on an empty stomach. Take drug after an overnight fast, 30 minutes before food. Food decreases drug exposure.
  • Take with or without food. Grapefruit may decrease mavorixafor metabolism and increase the risk of drug adverse reactions.

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as aminoquinolines and derivatives. These are organic compounds containing an amino group attached to a quinoline ring system.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Aminoquinolines and derivatives
Direct Parent
Aminoquinolines and derivatives
Alternative Parents
Hydroquinolines / Benzimidazoles / Aralkylamines / Pyridines and derivatives / Benzenoids / Imidazoles / Heteroaromatic compounds / Trialkylamines / Azacyclic compounds / Monoalkylamines
show 1 more
Substituents
Amine / Aminoquinoline / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenoid / Benzimidazole / Heteroaromatic compound / Hydrocarbon derivative
show 9 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
0G9LGB5O2W
CAS number
558447-26-0
InChI Key
WVLHHLRVNDMIAR-IBGZPJMESA-N
InChI
InChI=1S/C21H27N5/c22-12-3-4-14-26(15-20-24-17-9-1-2-10-18(17)25-20)19-11-5-7-16-8-6-13-23-21(16)19/h1-2,6,8-10,13,19H,3-5,7,11-12,14-15,22H2,(H,24,25)/t19-/m0/s1
IUPAC Name
(8S)-N-(4-aminobutyl)-N-[(1H-1,3-benzodiazol-2-yl)methyl]-5,6,7,8-tetrahydroquinolin-8-amine
SMILES
NCCCCN(CC1=NC2=CC=CC=C2N1)[C@H]1CCCC2=C1N=CC=C2

References

General References
  1. Stone ND, Dunaway SB, Flexner C, Tierney C, Calandra GB, Becker S, Cao YJ, Wiggins IP, Conley J, MacFarland RT, Park JG, Lalama C, Snyder S, Kallungal B, Klingman KL, Hendrix CW: Multiple-dose escalation study of the safety, pharmacokinetics, and biologic activity of oral AMD070, a selective CXCR4 receptor inhibitor, in human subjects. Antimicrob Agents Chemother. 2007 Jul;51(7):2351-8. Epub 2007 Apr 23. [Article]
  2. Andtbacka RHI, Wang Y, Pierce RH, Campbell JS, Yushak M, Milhem M, Ross M, Niland K, Arbeit RD, Parasuraman S, Bickley K, Yeung CC, Aicher LD, Smythe KS, Gan L: Mavorixafor, an Orally Bioavailable CXCR4 Antagonist, Increases Immune Cell Infiltration and Inflammatory Status of Tumor Microenvironment in Patients with Melanoma. Cancer Res Commun. 2022 Aug 31;2(8):904-913. doi: 10.1158/2767-9764.CRC-22-0090. eCollection 2022 Aug. [Article]
  3. Milanesi S, Locati M, Borroni EM: Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom's Macroglobulinemia. Int J Mol Sci. 2020 Aug 8;21(16):5696. doi: 10.3390/ijms21165696. [Article]
  4. Dale DC, Firkin F, Bolyard AA, Kelley M, Makaryan V, Gorelick KJ, Ebrahim T, Garg V, Tang W, Jiang H, Skerlj R, Beaussant Cohen S: Results of a phase 2 trial of an oral CXCR4 antagonist, mavorixafor, for treatment of WHIM syndrome. Blood. 2020 Dec 24;136(26):2994-3003. doi: 10.1182/blood.2020007197. [Article]
  5. Zmajkovicova K, Pawar S, Maier-Munsa S, Maierhofer B, Wiest I, Skerlj R, Taveras AG, Badarau A: Genotype-phenotype correlations in WHIM syndrome: a systematic characterization of CXCR4(WHIM) variants. Genes Immun. 2022 Sep;23(6):196-204. doi: 10.1038/s41435-022-00181-9. Epub 2022 Sep 12. [Article]
  6. FDA Approved Drug Products: XOLREMDI (mavorixafor) capsules, for oral use [Link]
  7. FDA: FDA approves first drug for WHIM syndrome, a rare disorder that can lead to recurrent, life-threatening infections [Link]
PubChem Compound
11256587
PubChem Substance
347827734
ChemSpider
9431613
BindingDB
50315305
ChEBI
138865
ChEMBL
CHEMBL518924
ZINC
ZINC000033359232
Wikipedia
Mavorixafor

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentWHIM Syndrome1
3Not Yet RecruitingTreatmentNeutropenia1
2CompletedTreatmentWHIM Syndrome1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / X4 Tropic Virus1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0284 mg/mLALOGPS
logP2.61ALOGPS
logP2.61Chemaxon
logS-4.1ALOGPS
pKa (Strongest Acidic)11.5Chemaxon
pKa (Strongest Basic)10.18Chemaxon
Physiological Charge2Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area70.83 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity104.49 m3·mol-1Chemaxon
Polarizability41.01 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
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/MSsplash10-0udi-0009000000-8ec41bdfc781460b4184
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0002-0129000000-2f1e27070ffb5d2bcc91
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0f89-0109000000-02d1bb52c4b3346bc09b
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0002-0139000000-d20eaef4e857f92f1541
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-0972000000-4fa38c8e2b096f1199aa
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0002-0900000000-544ec10b25a5f6740ecf
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-181.77473
predicted
DeepCCS 1.0 (2019)
[M+H]+184.13275
predicted
DeepCCS 1.0 (2019)
[M+Na]+191.79967
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Details1. C-X-C chemokine receptor type 4
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
Inhibitor
General Function
Virus receptor activity
Specific Function
Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation. Acts as a receptor for extracellular ubiq...
Gene Name
CXCR4
Uniprot ID
P61073
Uniprot Name
C-X-C chemokine receptor type 4
Molecular Weight
39745.055 Da
References
  1. Castillo JJ, Treon SP: Management of Waldenstrom macroglobulinemia in 2020. Hematology Am Soc Hematol Educ Program. 2020 Dec 4;2020(1):372-379. doi: 10.1182/hematology.2020000121. [Article]
  2. De Clercq E: Emerging anti-HIV drugs. Expert Opin Emerg Drugs. 2005 May;10(2):241-73. [Article]
  3. FDA Approved Drug Products: XOLREMDI (mavorixafor) capsules, for oral use [Link]

Enzymes

Details1. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
Mavorixafor is a time-dependent inhibitor of CYP3A4.
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: XOLREMDI (mavorixafor) capsules, for oral use [Link]
Details2. Cytochrome P450 2D6
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. FDA Approved Drug Products: XOLREMDI (mavorixafor) capsules, for oral use [Link]
Details3. Cytochrome P450 3A5
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Oxygen binding
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
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. FDA Approved Drug Products: XOLREMDI (mavorixafor) capsules, for oral use [Link]
Details4. Cytochrome P450 2C19
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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: XOLREMDI (mavorixafor) capsules, for oral use [Link]
Details5. Cytochrome P450 2B6
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. FDA Approved Drug Products: XOLREMDI (mavorixafor) capsules, for oral use [Link]
Details6. Cytochrome P450 1A2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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: XOLREMDI (mavorixafor) capsules, for oral use [Link]
Details7. Cytochrome P450 2C8
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. FDA Approved Drug Products: XOLREMDI (mavorixafor) capsules, for oral use [Link]
Details8. Cytochrome P450 2C9
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. FDA Approved Drug Products: XOLREMDI (mavorixafor) capsules, for oral use [Link]

Transporters

Details1. P-glycoprotein 1
Kind
Protein
Organism
Humans
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
References
  1. FDA Approved Drug Products: XOLREMDI (mavorixafor) capsules, for oral use [Link]
Details2. Solute carrier family 22 member 2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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: XOLREMDI (mavorixafor) capsules, for oral use [Link]
Details3. Multidrug and toxin extrusion protein 1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Monovalent cation:proton antiporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
References
  1. FDA Approved Drug Products: XOLREMDI (mavorixafor) capsules, for oral use [Link]

Drug created at November 18, 2007 18:25 / Updated at May 07, 2024 17:23