Odevixibat

Identification

Summary

Odevixibat is an ileal sodium/bile acid cotransporter inhibitor indicated in the treatment of pruritus in patients with progressive familial intrahepatic cholestasis.

Brand Names
Bylvay
Generic Name
Odevixibat
DrugBank Accession Number
DB16261
Background

Odevixibat, or A4250, is an ileal sodium/bile acid cotransporter inhibitor indicated for the treatment of pruritus in patients older than 3 months, with progressive familiar intrahepatic cholestasis (PFIC).1,5 Odevixibat is the first approved non-surgical treatment option for PFIC.7 Previous therapies for PFIC included a bile acid sequestrant such as ursodeoxycholic acid.1

Odevixibat was granted FDA approval on 20 July 2021.5

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 740.93
Monoisotopic: 740.29135687
Chemical Formula
C37H48N4O8S2
Synonyms
  • Odevixibat
External IDs
  • A-4250
  • A4250
  • AR-H064974
  • AZD-8294
  • AZD8294
  • WHO 10706

Pharmacology

Indication

Odevixibat is indicated for the treatment of pruritus in patients older than 3 months, with progressive familiar intrahepatic cholestasis (PFIC).5

It may not be effective in PFIC type 2 with ABCB11 variants.5 These patients lack a functional bile salt export pump.5

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Odevixibat, or A4250, is an ileal sodium/bile acid cotransporter inhibitor indicated for the treatment of pruritus in patients older than 3 months, with progressive familiar intrahepatic cholestasis (PFIC).1,5 It has a moderate duration of action as it is given once daily.5 Odevixibat has a wide therapeutic index as patients were given single doses up to 10 mg while the maximum therapeutic dose is 6 mg daily.1,5 Patients should be counselled regarding the risks of elevated liver function tests, diarrhea, and fat soluble vitamin defiencies.5

Mechanism of action

Progressive familiar intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders leading to cholestasis, fibrosis, and eventually a need for liver transplantation.2 Patients with PFIC require liver transplants or develop hepatocellular carcinomas in their first few years of life.2 Many of these patients experience severe pruritus.2 The exact mechanism of pruritus is PFIC is not known, but lower concentrations of bile acids have been shown to reduce pruritus.3,4,5 Patients with certain forms of PFIC type 2, associated with a non-functional or absent bile salt export pump, are not expected to benefit from odevixibat treatment.5

The ileal sodium/bile acid cotransporter is a transport glycoprotein responsible for reabsorption of 95% of bile acids in the distal ileum.1 Odevixibat is a reversible inhibitor of the ileal sodium/bile acid contransporter.1,5 Patients taking odevixibat for a week experienced a 56% reduction in bile acid area under the curve with a 3 mg once daily dose.1 A 1.5 mg daily dose lead to a 43% reduction in bile acid area under the curve.1

The decreased reabsorption of bile acids, leads to reduced stimulation of FXR, which reduces expression of FGF19, reducing binding of FGF19 to FGF4R, decreasing inhibition of bile acid synthesis.1 Further synthesis of bile acids that will not be reabsorbed in the intestine contributes to lowering low density lipoprotein levels.1

TargetActionsOrganism
AIleal sodium/bile acid cotransporter
inhibitor
Humans
Absorption

A 7.2 mg single oral dose of odevixibat in adults reaches a Cmax of 0.47 ng/mL, with an AUC0-24h of 2.19 h*ng/mL.5 The majority of adult and pediatric patients, given a therapeutic dose, do not have detectable plasma concentrations of odevixibat.1,5

Volume of distribution

The majority of adult and pediatric patients, given a therapeutic dose, do not have detectable plasma concentrations of odevixibat.1,5 Therefore, a volume of distribution has not been calculated.1,5

Protein binding

Due to the low systemic abosrption of odevixibat, plasma protein binding studies could not be performed in vivo.5 Odevixibat is >99% protein bound in vitro.5

Metabolism

Odevixibat is largely unmetabolized, however a small amount is metabolized in vitro by mono-hydroxylation.5 The exact structure of the metabolite has not been characterized as a primary endpoint of the clinical trial was to characterize the structure of metabolites accounting for >10% of the dose in plasma, urine, or feces.6 No metabolites have been identified at such a high concentration.5

Route of elimination

Odevixibat is 82.9% recovered in the feces and <0.002% recovered in the urine.5 The dose recovered in the feces is 97% unchanged parent compound.5

Half-life

A 7.2 mg oral dose of odevixibat has a mean half life of 2.36 hours in adults.5

Clearance

The majority of adult and pediatric patients, given a therapeutic dose, do not have detectable plasma concentrations of odevixibat.1,5 Therefore, the clearance has not been calculated.1,5

Adverse Effects
Adverseeffects
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Toxicity

Data regarding overdoses of odevixibat are not readily available, due to the low systemic absorption of the drug.5 If patients experience an overdose, initiate treatment with symptomatic and supportive measures.

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
CholestyramineThe therapeutic efficacy of Odevixibat can be decreased when used in combination with Cholestyramine.
ColesevelamThe therapeutic efficacy of Odevixibat can be decreased when used in combination with Colesevelam.
ColestipolThe therapeutic efficacy of Odevixibat can be decreased when used in combination with Colestipol.
SevelamerThe therapeutic efficacy of Odevixibat can be decreased when used in combination with Sevelamer.
Interactions
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Food Interactions
  • Take with a high fat meal. The effect of food is not clinically significant.

Products

Products2
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International/Other Brands
Bylvay (Albireo Pharma, Inc.)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
BylvayCapsule, coated pellets1200 ug/1OralAlbireo Pharma, Inc.2021-07-20Not applicableUS flag
BylvayCapsule, coated pellets200 ug/1OralAlbireo Pharma, Inc.2021-07-20Not applicableUS flag
BylvayCapsule, coated pellets600 ug/1OralAlbireo Pharma, Inc.2021-07-20Not applicableUS flag
BylvayCapsule, coated pellets400 ug/1OralAlbireo Pharma, Inc.2021-07-20Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans

Chemical Identifiers

UNII
2W150K0UUC
CAS number
501692-44-0
InChI Key
XULSCZPZVQIMFM-IPZQJPLYSA-N
InChI
InChI=1S/C37H48N4O8S2/c1-5-8-19-37(20-9-6-2)24-41(26-13-11-10-12-14-26)29-21-31(50-4)30(22-32(29)51(47,48)40-37)49-23-33(43)39-34(25-15-17-27(42)18-16-25)35(44)38-28(7-3)36(45)46/h10-18,21-22,28,34,40,42H,5-9,19-20,23-24H2,1-4H3,(H,38,44)(H,39,43)(H,45,46)/t28-,34+/m0/s1
IUPAC Name
(2S)-2-[(2R)-2-(2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1lambda6,2,5-benzothiadiazepin-8-yl]oxy}acetamido)-2-(4-hydroxyphenyl)acetamido]butanoic acid
SMILES
CCCCC1(CCCC)CN(C2=CC=CC=C2)C2=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C3=CC=C(O)C=C3)C=C2S(=O)(=O)N1

References

General References
  1. Graffner H, Gillberg PG, Rikner L, Marschall HU: The ileal bile acid transporter inhibitor A4250 decreases serum bile acids by interrupting the enterohepatic circulation. Aliment Pharmacol Ther. 2016 Jan;43(2):303-10. doi: 10.1111/apt.13457. Epub 2015 Nov 2. [Article]
  2. Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E: Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis. 2009 Jan 8;4:1. doi: 10.1186/1750-1172-4-1. [Article]
  3. Slavetinsky C, Sturm E: Odevixibat and partial external biliary diversion showed equal improvement of cholestasis in a patient with progressive familial intrahepatic cholestasis. BMJ Case Rep. 2020 Jun 29;13(6). pii: 13/6/e234185. doi: 10.1136/bcr-2019-234185. [Article]
  4. Al-Dury S, Marschall HU: Ileal Bile Acid Transporter Inhibition for the Treatment of Chronic Constipation, Cholestatic Pruritus, and NASH. Front Pharmacol. 2018 Aug 21;9:931. doi: 10.3389/fphar.2018.00931. eCollection 2018. [Article]
  5. FDA Approved Drug Products: Bylvay (Odevixibat) Oral Capsule [Link]
  6. Clinical Trials: NCT03082937 [Link]
  7. Globe Newswire: Albireo Announces FDA Approval of Bylvay (odevixibat), the First Drug Treatment for Patients With Progressive Familial Intrahepatic Cholestasis (PFIC) [Link]
ChemSpider
8329135
RxNav
2563966
ChEMBL
CHEMBL4297588
Wikipedia
Odevixibat

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentPFIC1 / PFIC21
3Not Yet RecruitingTreatmentAlagille Syndrome1
3RecruitingTreatmentAlagille Syndrome1
3RecruitingTreatmentBiliary Atresia1
3RecruitingTreatmentProgressive Familial Intrahepatic Cholestasis (PFIC)1
2CompletedTreatmentPediatric Cholestasis1
2TerminatedTreatmentPrimary Biliary Cholangitis1
2WithdrawnTreatmentFatty Liver, Non-alcoholic Fatty Liver Disease, NAFLD / Non Alcoholic Steatohepatitis (NASH)1
1CompletedTreatmentAlagille Syndrome / Orphan Cholestatic Liver Diseases / Primary Biliary Cholangitis / Progressive Familial Intrahepatic Cholestasis (PFIC)2
1CompletedTreatmentHealthy Subjects (HS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Capsule, coated pelletsOral1200 ug/1
Capsule, coated pelletsOral200 ug/1
Capsule, coated pelletsOral400 ug/1
Capsule, coated pelletsOral600 ug/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00115 mg/mLALOGPS
logP4.44ALOGPS
logP6.28ChemAxon
logS-5.8ALOGPS
pKa (Strongest Acidic)3.4ChemAxon
pKa (Strongest Basic)-3.4ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area174.37 Å2ChemAxon
Rotatable Bond Count17ChemAxon
Refractivity197.31 m3·mol-1ChemAxon
Polarizability80.03 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
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
Inhibitor
General Function
Bile acid:sodium symporter activity
Specific Function
Plays a critical role in the sodium-dependent reabsorption of bile acids from the lumen of the small intestine. Plays a key role in cholesterol metabolism.
Gene Name
SLC10A2
Uniprot ID
Q12908
Uniprot Name
Ileal sodium/bile acid cotransporter
Molecular Weight
37713.405 Da
References
  1. FDA Approved Drug Products: Bylvay (Odevixibat) Oral Capsule [Link]

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: Bylvay (Odevixibat) Oral Capsule [Link]

Drug created on December 15, 2020 18:17 / Updated on July 24, 2021 00:51