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

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Odevixibat (DB16261)

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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) and cholestatic pruritus in patients 12 months of age and older with Alagille Syndrome.⁹ It may not be effective in patients with PFIC type 2 with ABCB11 variants since these patients lack a functional bile salt export pump.⁵

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Associated Conditions

• Cholestatic pruritus
• Pruritus

Contraindications & Blackbox Warnings

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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

Target	Actions	Organism
AIleal sodium/bile acid cotransporter	inhibitor	Humans

Absorption

A 7.2 mg single oral dose of odevixibat in adults reaches a C_max of 0.47 ng/mL, with an AUC_0-24h 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

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Cholestyramine	The therapeutic efficacy of Odevixibat can be decreased when used in combination with Cholestyramine.
Colesevelam	The therapeutic efficacy of Odevixibat can be decreased when used in combination with Colesevelam.
Colestipol	The therapeutic efficacy of Odevixibat can be decreased when used in combination with Colestipol.
Sevelamer	The therapeutic efficacy of Odevixibat can be decreased when used in combination with Sevelamer.

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Food Interactions

• Take with a high fat meal. The effect of food is not clinically significant.

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International/Other Brands

Bylvay (Albireo Pharma, Inc.)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Bylvay	Capsule	600 µg	Oral	Albireo	2021-10-06	Not applicable
Bylvay	Capsule, coated pellets	1200 ug/1	Oral	Albireo Pharma, Inc.	2021-07-20	Not applicable
Bylvay	Capsule, coated pellets	200 ug/1	Oral	Albireo Pharma, Inc.	2021-07-20	Not applicable
Bylvay	Capsule	400 µg	Oral	Albireo	2021-10-06	Not applicable
Bylvay	Capsule, coated pellets	600 ug/1	Oral	Albireo Pharma, Inc.	2021-07-20	Not applicable
Bylvay	Capsule	1200 µg	Oral	Albireo	2021-10-06	Not applicable
Bylvay	Capsule	200 µg	Oral	Albireo	2021-10-06	Not applicable
Bylvay	Capsule, coated pellets	400 ug/1	Oral	Albireo Pharma, Inc.	2021-07-20	Not applicable

Categories

ATC Codes

A05AX05 — Odevixibat

• A05AX — Other drugs for bile therapy
• A05A — BILE THERAPY
• A05 — BILE AND LIVER THERAPY
• A — ALIMENTARY TRACT AND METABOLISM

Drug Categories

• Acids, Acyclic
• Alimentary Tract and Metabolism
• Benzazepines
• Bile and Liver Therapy
• Bile Therapy
• Fatty Acids
• Fatty Acids, Volatile
• Heterocyclic Compounds, Fused-Ring
• Ileal bile acid transport inhibitor
• Ileal Bile Acid Transporter Inhibitor
• Lipids
• P-glycoprotein substrates

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]
8. FDA Approved Drug Products: Bylvay (Odevixibat) Oral Capsule (May 2023) [Link]
9. FDA Approved Drug Products: Bylvay (Odevixibat) Oral Capsule (June 2023) [Link]

External Links

Human Metabolome Database

HMDB0304842

ChemSpider

8329135

BindingDB

77040

RxNav

2563966

ChEMBL

CHEMBL4297588

PharmGKB

PA166268805

Wikipedia

Odevixibat

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Alagille Syndrome	1
3	Active Not Recruiting	Treatment	Biliary Atresia	1
3	Active Not Recruiting	Treatment	Progressive Familial Intrahepatic Cholestasis (PFIC)	1
3	Completed	Treatment	Alagille Syndrome	1
3	Completed	Treatment	PFIC1 / PFIC2	1
3	Enrolling by Invitation	Treatment	Biliary Atresia	1
2	Completed	Treatment	Pediatric Cholestasis	1
2	Terminated	Treatment	Primary Biliary Cholangitis	1
2	Withdrawn	Treatment	Fatty Liver, Non-alcoholic Fatty Liver Disease, NAFLD / Non Alcoholic Steatohepatitis (NASH)	1
1	Completed	Treatment	Alagille Syndrome / Orphan Cholestatic Liver Diseases / Primary Biliary Cholangitis / Progressive Familial Intrahepatic Cholestasis (PFIC)	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral	1200 µg
Capsule	Oral	1200 MCG
Capsule	Oral	200 MCG
Capsule	Oral	200 µg
Capsule	Oral	400 µg
Capsule	Oral	400 MCG
Capsule	Oral	600 µg
Capsule	Oral	600 MCG
Capsule, coated pellets	Oral	1200 ug/1
Capsule, coated pellets	Oral	200 ug/1
Capsule, coated pellets	Oral	400 ug/1
Capsule, coated pellets	Oral	600 ug/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US10487111	No	2019-11-26	2031-11-08
US10981952	No	2021-04-20	2031-11-08
US9694018	No	2017-07-04	2031-11-08
US10011633	No	2018-07-03	2031-11-08
US10093697	No	2018-10-09	2031-11-08
US7132416	No	2006-11-07	2022-09-05
US10975046	No	2021-04-13	2039-06-20
US11365182	No	2019-06-20	2039-06-20
US11583539	No	2021-11-12	2041-11-12

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.00115 mg/mL	ALOGPS
logP	4.44	ALOGPS
logP	6.28	Chemaxon
logS	-5.8	ALOGPS
pKa (Strongest Acidic)	3.4	Chemaxon
pKa (Strongest Basic)	-3.4	Chemaxon
Physiological Charge	-1	Chemaxon
Hydrogen Acceptor Count	9	Chemaxon
Hydrogen Donor Count	5	Chemaxon
Polar Surface Area	174.37 Å2	Chemaxon
Rotatable Bond Count	17	Chemaxon
Refractivity	197.31 m3·mol-1	Chemaxon
Polarizability	80.03 Å3	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	0	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Targets

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Details1. Ileal sodium/bile acid cotransporter

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. Karpen SJ, Kelly D, Mack C, Stein P: Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders. Hepatol Int. 2020 Sep;14(5):677-689. doi: 10.1007/s12072-020-10070-w. Epub 2020 Jul 11. [Article]
2. FDA Approved Drug Products: Bylvay (Odevixibat) Oral Capsule [Link]

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Drug created at December 15, 2020 18:17 / Updated at June 17, 2023 00:12