Bexagliflozin

Identification

Summary

Bexagliflozin is a sodium-glucose co-transporter 2 inhibitor used to improve glycemic control in patients with type 2 diabetes mellitus.

Brand Names
Brenzavvy
Generic Name
Bexagliflozin
DrugBank Accession Number
DB12236
Background

Bexagliflozin is a highly specific and potent sodium-glucose co-transporter 2 (SGLT2) inhibitor.1,2,6 Similar to other SGLT2 inhibitors, bexagliflozin contains three basic moieties: glucose, two benzene rings and a methylene bridge.2 SGLT2 is responsible for 60% to 90% of renal glucose re-uptake, and unlike other isoforms such as SGLT1, SGLT2 is mainly expressed in the kidney.1 By inhibiting SGLT2, bexagliflozin reduces renal reabsorption of filtered glucose and increases urinary glucose excretion, which reduces blood glucose levels independently of insulin sensitivity.4,6 In January 2023, bexagliflozin was approved by the FDA for the treatment of adults with type 2 diabetes. Its use is not recommended in patients with type 1 diabetes since it may increase their risk of diabetic ketoacidosis.6

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 464.94
Monoisotopic: 464.160181
Chemical Formula
C24H29ClO7
Synonyms
  • (2S,3R,4R,5S,6R)-2-(4-chloro-3-((4-(2-(cyclopropyloxy)ethoxy)phenyl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
  • Bexagliflozin
  • D-glucitol, 1,5-anhydro-1-C-(4-chloro-3-((4-(2-(cyclopropyloxy)ethoxy)phenyl)methyl)phenyl)-, (1s)-
External IDs
  • EGT-1442
  • EGT0001442
  • EGT1442
  • THR-1442
  • THR1442

Pharmacology

Indication

Bexagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.6

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Adjunct therapy in management ofType 2 diabetes mellitus•••••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Healthy subjects and adults with type 2 diabetes mellitus given single or multiple doses of bexagliflozin had dose-dependent increases in urinary glucose excretion (UGE) accompanied by increases in urine volume. A 20 mg bexagliflozin dose can provide near-maximal UGE, and elevated UGE values are maintained with multiple-dose administration. Bexagliflozin does not cause clinically significant QTc interval prolongation at 5 times the recommended dose.6

The use of bexagliflozin may cause ketoacidosis, volume depletion, urosepsis, pyelonephritis, necrotizing fasciitis of the perineum and genital mycotic infections. There is also an increased incidence of lower limb amputation in patients treated with bexagliflozin compared to those receiving a placebo. In addition, the use of bexagliflozin in patients treated with insulin and insulin secretagogues may increase the risk of hypoglycemia.6

Mechanism of action

Bexagliflozin is a highly selective sodium–glucose co-transporter 2 (SGLT2) inhibitor. SGLT2 is located in the proximal renal tubule, a part of the kidney where most reabsorption takes place, and they transport glucose and sodium from the tubular lumen to the epithelium. By inhibiting SGLT2, bexagliflozin reduces glucose reabsorption in the kidney and promotes its excretion in urine. Therefore, in patients with type 2 diabetes mellitus (T2DM), bexagliflozin reduces blood glucose levels independently of insulin sensitivity.4,6

Aside from improving glycemic control, bexagliflozin may also reduce body weight, systolic blood pressure, and albuminuria.5 The mechanism of action for these other effects have not been fully elucidated, but it is possible that they depend on the initial natriuresis caused by bexagliflozin, followed by a change in tissue sodium handling.4

TargetActionsOrganism
ASodium/glucose cotransporter 2
inhibitor
Humans
Absorption

Healthy subjects and adult patients with type 2 diabetes mellitus given bexagliflozin have similar pharmacokinetic profiles. In a fasted state, the mean Cmax and AUC0-∞ of bexagliflozin were 134 ng/mL and 1,162 ng·h/mL, respectively. Bexagliflozin does not follow a time-dependent pharmacokinetic profile, and after multiple doses, approximately up to 20% is accumulated in plasma. The peak plasma concentration of bexagliflozin is reached between 2 and 4 hours after oral administration. This timing can be delayed if bexagliflozin is taken after a meal or with medications that slow gastric emptying. Between single doses of 3 mg and 90 mg (0.15 to 4.5 times the recommended dose), the plasma Cmax and AUC of bexagliflozin increase in a dose-proportional manner.6

Compared to dosing in the fasted state, consuming a standard high-fat, high-caloric meal leads to a 31% and 10% higher Cmax and AUC, respectively. Under these conditions, the median Tmax was increased to 5 hours. The effects of food on bexagliflozin pharmacokinetics are not considered clinically relevant.6

Volume of distribution

Bexagliflozin has an apparent volume of distribution of 262 L.6

Protein binding

Approximately 93% of bexagliflozin is bound to plasma protein.6

Metabolism

Bexagliflozin is metabolized in the liver mainly by UGT1A9 and, to a lesser extent, CYP3A. In healthy volunteers given an oral [14C]-bexagliflozin solution, the 3'-O-glucuronide, a pharmacologically inactive metabolite, constituted 32.2% of the parent compound AUC. The rest of the bexagliflozin metabolites contributed less than 10% of the parent AUC. None of the metabolites are expected to have clinically relevant pharmacological effects.3,6

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Route of elimination

Bexagliflozin is mainly eliminated through feces and urine. In healthy subjects given an oral [14C]-bexagliflozin solution, 91.6% of input radioactivity was recovered. Of this amount, 51.1% was recovered in feces, mainly as the parent compound, while 40.5% was recovered in urine, mostly as the 3'-O-glucuronide. The proportions of input radioactivity recovered as bexagliflozin in urine and feces were 1.5% and 28.7%, respectively.6

Half-life

Bexagliflozin has an apparent terminal elimination half-life of approximately 12 hours.6

Clearance

Population pharmacokinetic modeling has shown that the apparent oral clearance of bexagliflozin is 19.1 L/h.6

Adverse Effects
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Toxicity

In case of a bexagliflozin overdose, the FDA product label recommends contacting the Poison Help line or a medical toxicologist for additional overdosage management recommendations. Usual supportive measures based on the patient’s clinical status should be employed. The removal of bexagliflozin by hemodialysis has not been evaluated.6 Carcinogenicity was evaluated in mice and rats, and no drug-related neoplastic findings were reported at up to the highest doses, which corresponded to 156 times (mice) and 68 times (rats) the clinical dose of bexagliflozin (20 mg) based on AUC. In vitro and in vivo studies found that bexagliflozin was not mutagenic or clastogenic. Fertility studies done in male and female rats showed that bexagliflozin had no effects on mating, fertility or early embryonic development at up to 200 mg/kg/day, which corresponded to 280 and 439 times the clinical dose of bexagliflozin in males and females, respectively.6

Pathways
Not Available
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
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
AcarboseBexagliflozin may increase the hypoglycemic activities of Acarbose.
AcebutololThe therapeutic efficacy of Bexagliflozin can be increased when used in combination with Acebutolol.
AcetazolamideThe therapeutic efficacy of Bexagliflozin can be increased when used in combination with Acetazolamide.
AcetohexamideBexagliflozin may increase the hypoglycemic activities of Acetohexamide.
Acetyl sulfisoxazoleThe therapeutic efficacy of Bexagliflozin can be increased when used in combination with Acetyl sulfisoxazole.
Food Interactions
  • Take with or without food. Peak plasma concentrations of bexagliflozin can be delayed if taken after a meal; however, the effects of food on bexagliflozin pharmacokinetics are not considered clinically relevant.

Products

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International/Other Brands
Brenzavvy (TheracosBio)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
BrenzavvyTablet20 mg/1OralGolden State Medical Supply, Inc.2023-01-20Not applicableUS flag
BrenzavvyTablet20 mg/1OralTheracosBio, LLC2023-07-13Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenolic glycosides. These are organic compounds containing a phenolic structure attached to a glycosyl moiety. Some examples of phenolic structures include lignans, and flavonoids. Among the sugar units found in natural glycosides are D-glucose, L-Fructose, and L rhamnose.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Carbohydrates and carbohydrate conjugates
Direct Parent
Phenolic glycosides
Alternative Parents
Diphenylmethanes / Hexoses / C-glycosyl compounds / Phenoxy compounds / Phenol ethers / Alkyl aryl ethers / Chlorobenzenes / Oxanes / Aryl chlorides / 1,2-diols
show 6 more
Substituents
1,2-diol / Alcohol / Alkyl aryl ether / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Benzenoid / C-glycosyl compound / Chlorobenzene / Dialkyl ether
show 18 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
EY00JF42FV
CAS number
1118567-05-7
InChI Key
BTCRKOKVYTVOLU-SJSRKZJXSA-N
InChI
InChI=1S/C24H29ClO7/c25-19-8-3-15(24-23(29)22(28)21(27)20(13-26)32-24)12-16(19)11-14-1-4-17(5-2-14)30-9-10-31-18-6-7-18/h1-5,8,12,18,20-24,26-29H,6-7,9-11,13H2/t20-,21-,22+,23-,24+/m1/s1
IUPAC Name
(2S,3R,4R,5S,6R)-2-(4-chloro-3-{[4-(2-cyclopropoxyethoxy)phenyl]methyl}phenyl)-6-(hydroxymethyl)oxane-3,4,5-triol
SMILES
OC[C@H]1O[C@H]([C@H](O)[C@@H](O)[C@@H]1O)C1=CC=C(Cl)C(CC2=CC=C(OCCOC3CC3)C=C2)=C1

References

Synthesis Reference

Gharpure, M., et al. (2018). A process for the preparation of SGLT2 inhibitor and intermediates thereof (WO 2018/207113 A1). World Intellectual Property Organization. https://patentimages.storage.googleapis.com/8a/8f/d2/343c7232594398/WO2018207113A1.pdf

General References
  1. Zhang W, Welihinda A, Mechanic J, Ding H, Zhu L, Lu Y, Deng Z, Sheng Z, Lv B, Chen Y, Roberge JY, Seed B, Wang YX: EGT1442, a potent and selective SGLT2 inhibitor, attenuates blood glucose and HbA(1c) levels in db/db mice and prolongs the survival of stroke-prone rats. Pharmacol Res. 2011 Apr;63(4):284-93. doi: 10.1016/j.phrs.2011.01.001. Epub 2011 Jan 5. [Article]
  2. Azzam O, Carnagarin R, Lugo-Gavidia LM, Nolde J, Matthews VB, Schlaich MP: Bexagliflozin for type 2 diabetes: an overview of the data. Expert Opin Pharmacother. 2021 Nov;22(16):2095-2103. doi: 10.1080/14656566.2021.1959915. Epub 2021 Jul 29. [Article]
  3. Zhang W, Li X, Ding H, Lu Y, Stilwell GE, Halvorsen YD, Welihinda A: Metabolism and disposition of the SGLT2 inhibitor bexagliflozin in rats, monkeys and humans. Xenobiotica. 2020 May;50(5):559-569. doi: 10.1080/00498254.2019.1654634. Epub 2019 Aug 27. [Article]
  4. Cowie MR, Fisher M: SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol. 2020 Dec;17(12):761-772. doi: 10.1038/s41569-020-0406-8. Epub 2020 Jul 14. [Article]
  5. Allegretti AS, Zhang W, Zhou W, Thurber TK, Rigby SP, Bowman-Stroud C, Trescoli C, Serusclat P, Freeman MW, Halvorsen YC: Safety and Effectiveness of Bexagliflozin in Patients With Type 2 Diabetes Mellitus and Stage 3a/3b CKD. Am J Kidney Dis. 2019 Sep;74(3):328-337. doi: 10.1053/j.ajkd.2019.03.417. Epub 2019 May 14. [Article]
  6. FDA Approved Drug Products: BRENZAVVY (bexagliflozin) tablets for oral use [Link]
PubChem Compound
25195624
PubChem Substance
347828515
ChemSpider
26609013
BindingDB
50349249
RxNav
2627044
ChEMBL
CHEMBL1808388
ZINC
ZINC000059047505
Wikipedia
Bexagliflozin

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
4Not Yet RecruitingTreatmentSleep Apnea1
3CompletedTreatmentType 2 Diabetes Mellitus6
3RecruitingTreatmentType 2 Diabetes Mellitus1
2CompletedTreatmentDiabetes Mellitus1
2CompletedTreatmentType 2 Diabetes Mellitus2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral20 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US10533032No2020-01-142031-07-03US flag
US8802637No2014-08-122028-08-22US flag
US8106021No2012-01-312028-08-22US flag
US7838499No2010-11-232029-01-30US flag
US8987323No2015-03-242032-05-14US flag
US10981942No2021-04-202031-06-13US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySlightly solubleFDA label
Predicted Properties
PropertyValueSource
Water Solubility0.0565 mg/mLALOGPS
logP2.33ALOGPS
logP2.17Chemaxon
logS-3.9ALOGPS
pKa (Strongest Acidic)12.57Chemaxon
pKa (Strongest Basic)-3Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count7Chemaxon
Hydrogen Donor Count4Chemaxon
Polar Surface Area108.61 Å2Chemaxon
Rotatable Bond Count9Chemaxon
Refractivity118.44 m3·mol-1Chemaxon
Polarizability49.38 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/MSsplash10-014j-4004900000-06fbcebcf1cd445cfbaa
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0bti-5009500000-b024a6d4339c7f287446
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a6r-1014900000-260def8cddf68decee41
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-01q9-9007200000-d822f4e164e6c7bd83d4
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-052b-6396500000-20b44dbbab012b04bae0
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-057i-9054100000-4394c494593ef6a411be
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]-204.12209
predicted
DeepCCS 1.0 (2019)
[M+H]+206.4066
predicted
DeepCCS 1.0 (2019)
[M+Na]+212.31992
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Low-affinity glucose:sodium symporter activity
Specific Function
Sodium-dependent glucose transporter. Has a Na(+) to glucose coupling ratio of 1:1.Efficient substrate transport in mammalian kidney is provided by the concerted action of a low affinity high capac...
Gene Name
SLC5A2
Uniprot ID
P31639
Uniprot Name
Sodium/glucose cotransporter 2
Molecular Weight
72895.995 Da
References
  1. Zhang W, Welihinda A, Mechanic J, Ding H, Zhu L, Lu Y, Deng Z, Sheng Z, Lv B, Chen Y, Roberge JY, Seed B, Wang YX: EGT1442, a potent and selective SGLT2 inhibitor, attenuates blood glucose and HbA(1c) levels in db/db mice and prolongs the survival of stroke-prone rats. Pharmacol Res. 2011 Apr;63(4):284-93. doi: 10.1016/j.phrs.2011.01.001. Epub 2011 Jan 5. [Article]
  2. Azzam O, Carnagarin R, Lugo-Gavidia LM, Nolde J, Matthews VB, Schlaich MP: Bexagliflozin for type 2 diabetes: an overview of the data. Expert Opin Pharmacother. 2021 Nov;22(16):2095-2103. doi: 10.1080/14656566.2021.1959915. Epub 2021 Jul 29. [Article]
  3. FDA Approved Drug Products: BRENZAVVY (bexagliflozin) tablets for oral use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da
References
  1. Zhang W, Li X, Ding H, Lu Y, Stilwell GE, Halvorsen YD, Welihinda A: Metabolism and disposition of the SGLT2 inhibitor bexagliflozin in rats, monkeys and humans. Xenobiotica. 2020 May;50(5):559-569. doi: 10.1080/00498254.2019.1654634. Epub 2019 Aug 27. [Article]
  2. FDA Approved Drug Products: BRENZAVVY (bexagliflozin) tablets for oral use [Link]
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. Zhang W, Li X, Ding H, Lu Y, Stilwell GE, Halvorsen YD, Welihinda A: Metabolism and disposition of the SGLT2 inhibitor bexagliflozin in rats, monkeys and humans. Xenobiotica. 2020 May;50(5):559-569. doi: 10.1080/00498254.2019.1654634. Epub 2019 Aug 27. [Article]
  2. FDA Approved Drug Products: BRENZAVVY (bexagliflozin) tablets for oral use [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
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Zhang W, Li X, Ding H, Lu Y, Stilwell GE, Halvorsen YD, Welihinda A: Metabolism and disposition of the SGLT2 inhibitor bexagliflozin in rats, monkeys and humans. Xenobiotica. 2020 May;50(5):559-569. doi: 10.1080/00498254.2019.1654634. Epub 2019 Aug 27. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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. Zhang W, Li X, Ding H, Lu Y, Stilwell GE, Halvorsen YD, Welihinda A: Metabolism and disposition of the SGLT2 inhibitor bexagliflozin in rats, monkeys and humans. Xenobiotica. 2020 May;50(5):559-569. doi: 10.1080/00498254.2019.1654634. Epub 2019 Aug 27. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. Zhang W, Li X, Ding H, Lu Y, Stilwell GE, Halvorsen YD, Welihinda A: Metabolism and disposition of the SGLT2 inhibitor bexagliflozin in rats, monkeys and humans. Xenobiotica. 2020 May;50(5):559-569. doi: 10.1080/00498254.2019.1654634. Epub 2019 Aug 27. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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: BRENZAVVY (bexagliflozin) tablets for oral use [Link]

Drug created at October 20, 2016 21:41 / Updated at June 06, 2023 12:13