Voxelotor

Identification

Summary

Voxelotor is a drug used to inhibit the polymerization of hemoglobin S, preventing the painful and sometimes lethal vaso-occlusive crises associated with sickle cell disease.

Brand Names
Oxbryta
Generic Name
Voxelotor
DrugBank Accession Number
DB14975
Background

Voxelotor is a novel hemoglobin S polymerization inhibitor for the treatment of sickle cell disease. This is a genetically inherited condition most prevalent in the Middle East, Africa, and certain parts of India. Sickle cell disease can lead to excruciating pain, stroke, infection, and various other complications arising from the blockage of blood vessels.6

Voxelotor was granted accelerated FDA approval on November 25 2019, as it likely to be a promising treatment for the 100,000 individuals in the U.S. suffering from the disease, in addition to 20 million others worldwide.9 It was developed by Global Blood Therapeutics, Inc.9 and is unique from other drugs used to treat sickle cell anemia, such as hydroxyurea, L-glutamine, and crizanlizumab5 due to its novel mechanism of action.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 337.379
Monoisotopic: 337.142641484
Chemical Formula
C19H19N3O3
Synonyms
  • Voxelotor
  • Voxélotor
  • Voxelotorum
External IDs
  • GBT-440
  • GBT440
  • GTX-011

Pharmacology

Indication

Voxelotor is indicated to treat sickle cell disease in both adult and pediatric patients aged 12 years and above.7

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Voxelotor modifies hemoglobin to prevent painful and dangerous sickle cell crises that normally lead to organ damage, hospitalization, and sometimes death.6 It prevents low hemoglobin, which is normally associated with the destruction of sickled blood cells in sickle cell disease. Voxelotor has led to up to a 40% increase in hemoglobin in clinical trials.1,2

Mechanism of action

Deoxygenated sickle hemoglobin (HbS) polymerization is the causal factor for sickle cell disease. The genetic mutation associated with this disease leads to the formation of abnormal, sickle shaped red blood cells that aggregate and block blood vessels throughout the body, causing vaso-occlusive crises.6 Voxelotor binds irreversibly with the N‐terminal valine of the α‐chain of hemoglobin, leading to an allosteric modification of Hb20, which increases the affinity for oxygen. Oxygenated HbS does not polymerize.2,3 By directly blocking HbS polymerization, voxelotor can successfully treat sickle cell disease by preventing the formation of abnormally shaped cells, which eventually cause lack of oxygenation and blood flow to organs.1,5,6

TargetActionsOrganism
AHemoglobin subunit alpha
binder
Humans
Absorption

Voxelotor is rapidly absorbed after oral administration, with a plasma Tmax of 2 hours.2,10 Tmax in the red blood cells ranges from 17-24 hours.2 The Cmax, on average in whole blood and red blood cells occur 6 and 18 hours after an oral dose, respectively. Consumption of a high fat meal with voxelotor significantly increased exposure to the drug during clinical trials.7 After a daily dose of either 300, 600, or 900 mg for a period of 15 days, when steady-state concentrations were reached, the average RBC Cmax for the respective doses were measured to be 4950, 9610 and 14 000 μg*h mL−1, respectively.2

Volume of distribution

The apparent volume of distribution of voxelotor in the central compartment is 338L and 72.2L in the plasma.7

Protein binding

The protein binding of voxeletor is 99.8%, according to in vitro studies.7

Metabolism

Voxeletor is heavily metabolized via 2 phases. Phase I consists of oxidation and reduction, while phase II consists of glucuronidation. Voseletor is oxidized mainly by CYP3A4, and to a lesser extent by CYP2C19, CYP2B6, and CYP2C9 hepatic cytochrome enzymes.7,10

Route of elimination

62.6% of the voxelotor dose administered orally as well as its metabolites are found in the feces (with 33.3% as unchanged drug) and 35.5% in urine (with only 0.08% unchanged drug).2,7,10

Half-life

The plasma elimination half-life of voxelotor in sickle cell disease patients is about 35.5 hours, according to the FDA label.7 The mean half-life in the red blood cell is 60 days. The average plasma half-life of voxelotor was 50 hours in patients with sickle cell disease, compared with 61–85 hours in healthy patients, in one clinical study.2

Clearance

The apparent oral clearance of voxelotor is approximately 6.7 L/h.7

Adverse Effects
Adverseeffects
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Toxicity

LD50 information and overdose information is unavailable at this time. Dose-limiting toxicities are unlikely, based on the results of clinical studies.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
AbametapirThe serum concentration of Voxelotor can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Voxelotor can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Voxelotor.
AbirateroneThe serum concentration of Voxelotor can be increased when it is combined with Abiraterone.
AcalabrutinibThe serum concentration of Acalabrutinib can be increased when it is combined with Voxelotor.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Voxelotor.
AcetaminophenThe serum concentration of Voxelotor can be increased when it is combined with Acetaminophen.
AcetazolamideThe serum concentration of Voxelotor can be increased when it is combined with Acetazolamide.
AcetohexamideThe metabolism of Voxelotor can be decreased when combined with Acetohexamide.
Acetyl sulfisoxazoleThe metabolism of Voxelotor can be decreased when combined with Acetyl sulfisoxazole.
Interactions
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Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of voxelotor.
  • Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of voxelotor.
  • Take with or without food.

Products

Products2
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
OxbrytaTablet, film coated500 mg/1OralGlobal Blood Therapeutics Inc.2019-11-25Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as hydroxybenzaldehydes. These are organic aromatic compounds containing a benzene ring carrying an aldehyde group and a hydroxyl group.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Carbonyl compounds
Direct Parent
Hydroxybenzaldehydes
Alternative Parents
Phenoxy compounds / Phenol ethers / Benzoyl derivatives / Alkyl aryl ethers / 1-hydroxy-4-unsubstituted benzenoids / 1-hydroxy-2-unsubstituted benzenoids / Pyridines and derivatives / Vinylogous acids / Pyrazoles / Heteroaromatic compounds
show 4 more
Substituents
1-hydroxy-2-unsubstituted benzenoid / 1-hydroxy-4-unsubstituted benzenoid / Alkyl aryl ether / Aromatic heteromonocyclic compound / Azacycle / Azole / Benzenoid / Benzoyl / Ether / Heteroaromatic compound
show 13 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
3ZO554A4Q8
CAS number
1446321-46-5
InChI Key
FWCVZAQENIZVMY-UHFFFAOYSA-N
InChI
InChI=1S/C19H19N3O3/c1-13(2)22-16(8-10-21-22)19-14(5-4-9-20-19)12-25-18-7-3-6-17(24)15(18)11-23/h3-11,13,24H,12H2,1-2H3
IUPAC Name
2-hydroxy-6-({2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl}methoxy)benzaldehyde
SMILES
CC(C)N1N=CC=C1C1=C(COC2=CC=CC(O)=C2C=O)C=CC=N1

References

Synthesis Reference

Zhe Li, Nathan Guz, Yiyang Shao, Julieana Cocuz, Markus Frieser, George Petros Yiannikouros, Liang Liao.(2017).US10077249B2.Retrieved from: https://patents.google.com/patent/US10077249B2/en

General References
  1. Vichinsky E, Hoppe CC, Ataga KI, Ware RE, Nduba V, El-Beshlawy A, Hassab H, Achebe MM, Alkindi S, Brown RC, Diuguid DL, Telfer P, Tsitsikas DA, Elghandour A, Gordeuk VR, Kanter J, Abboud MR, Lehrer-Graiwer J, Tonda M, Intondi A, Tong B, Howard J: A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. N Engl J Med. 2019 Aug 8;381(6):509-519. doi: 10.1056/NEJMoa1903212. Epub 2019 Jun 14. [Article]
  2. Hutchaleelaha A, Patel M, Washington C, Siu V, Allen E, Oksenberg D, Gretler DD, Mant T, Lehrer-Graiwer J: Pharmacokinetics and pharmacodynamics of voxelotor (GBT440) in healthy adults and patients with sickle cell disease. Br J Clin Pharmacol. 2019 Jun;85(6):1290-1302. doi: 10.1111/bcp.13896. Epub 2019 Mar 31. [Article]
  3. Howard J, Hemmaway CJ, Telfer P, Layton DM, Porter J, Awogbade M, Mant T, Gretler DD, Dufu K, Hutchaleelaha A, Patel M, Siu V, Dixon S, Landsman N, Tonda M, Lehrer-Graiwer J: A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease. Blood. 2019 Apr 25;133(17):1865-1875. doi: 10.1182/blood-2018-08-868893. Epub 2019 Jan 17. [Article]
  4. Torres L, Conran N: Emerging pharmacotherapeutic approaches for the management of sickle cell disease. Expert Opin Pharmacother. 2019 Feb;20(2):173-186. doi: 10.1080/14656566.2018.1548610. Epub 2018 Nov 30. [Article]
  5. Ataga KI, Desai PC: Advances in new drug therapies for the management of sickle cell disease. Expert Opin Orphan Drugs. 2018;6(5):329-343. doi: 10.1080/21678707.2018.1471983. Epub 2018 May 14. [Article]
  6. Ankit Mangla; Moavia Ehsan; Smita Maruvada (2019). Sickle Cell Anemia. Stat Pearls.
  7. FDA Approved Drug Products: Oxbrytatm (voxelotor) tablets [Link]
  8. FDA approves novel treatment to target abnormality in sickle cell disease [Link]
  9. FDA approves Global Blood Therapeutics sickle cell disease drug [Link]
  10. Absorption, Metabolism and Excretion of GBT440, a Novel Hemoglobin S (HbS) Polymerization Inhibitor for the Treatment of Sickle Cell Disease (SCD), in Healthy Male Subjects [Link]
ChemSpider
37999268
BindingDB
50235297
RxNav
2265678
ChEMBL
CHEMBL4101807
ZINC
ZINC000145969085
Wikipedia
Voxelotor
MSDS
Download (175 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentSickle Cell Anemia1
4RecruitingTreatmentSickle Cell Anemia / Sickle Cell Disease (SCD)1
3Active Not RecruitingTreatmentSickle Cell Disease (SCD)1
3CompletedTreatmentSickle Cell Disease (SCD)1
3Enrolling by InvitationTreatmentSickle Cell Disease (SCD)1
3RecruitingTreatmentSickle Cell Disease (SCD)1
2CompletedOtherSickle Cell Disease (SCD)1
2CompletedSupportive CareHypoxemia / Idiopathic Pulmonary Fibrosis (IPF)1
2Not Yet RecruitingSupportive CareSickle Cell Anemia in Children1
2RecruitingTreatmentSickle Cell Disease (SCD)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral500 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US10017491No2018-07-102032-12-28US flag
US9447071No2016-09-202035-02-06US flag
US10034879No2018-07-312032-12-28US flag
US9018210No2015-04-282032-12-28US flag
US10493035No2019-12-032037-10-12US flag
US9248199No2016-02-022034-01-29US flag
US10722502No2015-02-062035-02-06US flag
US10806733No2012-12-282032-12-28US flag
US11020382No2016-12-022036-12-02US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)80-82http://drugapprovalsint.com/voxelotor/
boiling point (°C)539.2±50.0https://www.chemsrc.com/en/cas/1446321-46-5_1467959.html
water solubilityinsoluble in waterhttps://www.selleckchem.com/products/gbt440.html
logP2.85https://www.chemsrc.com/en/cas/1446321-46-5_1467959.html
pKa7.67±0.10https://www.chemicalbook.com/ChemicalProductProperty_EN_CB73053893.htm
Predicted Properties
PropertyValueSource
Water Solubility0.0526 mg/mLALOGPS
logP3.02ALOGPS
logP3.54ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)8.46ChemAxon
pKa (Strongest Basic)3.41ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area77.24 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity106.25 m3·mol-1ChemAxon
Polarizability35.37 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
Curator comments
Voxelotor binds with the N-terminal valine on the α chain of hemoglobin.
General Function
Oxygen transporter activity
Specific Function
Involved in oxygen transport from the lung to the various peripheral tissues.
Gene Name
HBA1
Uniprot ID
P69905
Uniprot Name
Hemoglobin subunit alpha
Molecular Weight
15257.405 Da
References
  1. Howard J, Hemmaway CJ, Telfer P, Layton DM, Porter J, Awogbade M, Mant T, Gretler DD, Dufu K, Hutchaleelaha A, Patel M, Siu V, Dixon S, Landsman N, Tonda M, Lehrer-Graiwer J: A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease. Blood. 2019 Apr 25;133(17):1865-1875. doi: 10.1182/blood-2018-08-868893. Epub 2019 Jan 17. [Article]
  2. FDA Approved Drug Products: Oxbrytatm (voxelotor) tablets [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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: Oxbrytatm (voxelotor) tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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: Oxbrytatm (voxelotor) tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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: Oxbrytatm (voxelotor) tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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: Oxbrytatm (voxelotor) tablets [Link]

Drug created on May 20, 2019 14:39 / Updated on August 07, 2021 00:12