MARALIXIBAT CHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C40H56N3O4S.Cl
Molecular Weight	710.408
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

[Cl-].CCCCC1(CCCC)CS(=O)(=O)C2=C(C=C(C=C2)N(C)C)[C@H]([C@H]1O)C3=CC=C(OCC4=CC=C(C[N+]56CCN(CC5)CC6)C=C4)C=C3

InChI

InChIKey=POMVPJBWDDJCMP-RUKDTIIFSA-M

InChI=1S/C40H56N3O4S.ClH/c1-5-7-19-40(20-8-6-2)30-48(45,46)37-18-15-34(41(3)4)27-36(37)38(39(40)44)33-13-16-35(17-14-33)47-29-32-11-9-31(10-12-32)28-43-24-21-42(22-25-43)23-26-43;/h9-18,27,38-39,44H,5-8,19-26,28-30H2,1-4H3;1H/q+1;/p-1/t38-,39-;/m1./s1

HIDE SMILES / InChI

Description

Maralixibat (Livmarli™) is a potent, apical, sodium‐dependent, bile acid transporter competitive inhibitor with minimal systemic absorption being developed by Mirum Pharmaceuticals for the treatment of rare cholestatic liver diseases including Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC) and biliary atresia. Maralixibat received its first approval on 29 September 2021, in the USA, for use in the treatment of cholestatic pruritus in patients with ALGS 1 year of age and older. Maralixibat is also under regulatory review for ALGS in Europe, and clinical development for cholestatic liver disorders including ALGS in patients under 1 year of age, PFIC and biliary atresia is continuing in several other countries. This article summarises the milestones in the development of maralixibat leading to this first approval for ALGS.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Ileal bile acid transporter 5	Inhibitor 8,504		0.3 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Cholestatic pruritus in patients with Alagille syndrome 2	Primary		Approved 8,583	Livmarli

C_max

Value	Dose	Analyte	Population
0.454 ng/mL	10 mg single, oral	MARALIXIBAT plasma	Homo sapiens
0.081 ng/mL	20 mg single, oral	MARALIXIBAT plasma	Homo sapiens
0.31 ng/mL	50 mg single, oral	MARALIXIBAT plasma	Homo sapiens
0.727 ng/mL	100 mg single, oral	MARALIXIBAT plasma	Homo sapiens
2.078 ng/mL	300 mg single, oral	MARALIXIBAT plasma	Homo sapiens
2.401 ng/mL	500 mg single, oral	MARALIXIBAT plasma	Homo sapiens
0.032 ng/mL	5 mg 1 times / day multiple, oral	MARALIXIBAT plasma	Homo sapiens
0.129 ng/mL	10 mg 1 times / day multiple, oral	MARALIXIBAT plasma	Homo sapiens
0.376 ng/mL	20 mg 1 times / day multiple, oral	MARALIXIBAT plasma	Homo sapiens
0.31 ng/mL	20 mg 1 times / day multiple, oral	MARALIXIBAT plasma	Homo sapiens
0.781 ng/mL	60 mg 1 times / day multiple, oral	MARALIXIBAT plasma	Homo sapiens
1.146 ng/mL	100 mg 1 times / day multiple, oral	MARALIXIBAT plasma	Homo sapiens
1.27 ng/mL	30 mg single, oral	MARALIXIBAT plasma	Homo sapiens
0.437 ng/mL	30 mg single, oral	MARALIXIBAT plasma	Homo sapiens
1.5 ng/mL	45 mg single, oral	MARALIXIBAT plasma	Homo sapiens
0.564 ng/mL	45 mg single, oral	MARALIXIBAT plasma	Homo sapiens
3.05 ng/mL	100 mg single, oral	MARALIXIBAT plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
0.946 ng × h/mL	10 mg single, oral	MARALIXIBAT plasma	Homo sapiens
0.161 ng × h/mL	20 mg single, oral	MARALIXIBAT plasma	Homo sapiens
0.6 ng × h/mL	50 mg single, oral	MARALIXIBAT plasma	Homo sapiens
1.668 ng × h/mL	100 mg single, oral	MARALIXIBAT plasma	Homo sapiens
7.51 ng × h/mL	300 mg single, oral	MARALIXIBAT plasma	Homo sapiens
14.191 ng × h/mL	500 mg single, oral	MARALIXIBAT plasma	Homo sapiens
0.032 ng × h/mL	5 mg 1 times / day multiple, oral	MARALIXIBAT plasma	Homo sapiens
0.248 ng × h/mL	10 mg 1 times / day multiple, oral	MARALIXIBAT plasma	Homo sapiens
1.152 ng × h/mL	20 mg 1 times / day multiple, oral	MARALIXIBAT plasma	Homo sapiens
0.424 ng × h/mL	20 mg 1 times / day multiple, oral	MARALIXIBAT plasma	Homo sapiens
5 ng × h/mL	60 mg 1 times / day multiple, oral	MARALIXIBAT plasma	Homo sapiens
4.614 ng × h/mL	100 mg 1 times / day multiple, oral	MARALIXIBAT plasma	Homo sapiens
2.24 ng × h/mL	30 mg single, oral	MARALIXIBAT plasma	Homo sapiens
0.514 ng × h/mL	30 mg single, oral	MARALIXIBAT plasma	Homo sapiens
3.07 ng × h/mL	45 mg single, oral	MARALIXIBAT plasma	Homo sapiens
1.4 ng × h/mL	45 mg single, oral	MARALIXIBAT plasma	Homo sapiens
10.2 ng × h/mL	100 mg single, oral	MARALIXIBAT plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
2.023 h	300 mg single, oral	MARALIXIBAT plasma	Homo sapiens
3.791 h	500 mg single, oral	MARALIXIBAT plasma	Homo sapiens
1.275 h	20 mg 1 times / day multiple, oral	MARALIXIBAT plasma	Homo sapiens
4.367 h	60 mg 1 times / day multiple, oral	MARALIXIBAT plasma	Homo sapiens
4.282 h	100 mg 1 times / day multiple, oral	MARALIXIBAT plasma	Homo sapiens
1.61 h	30 mg single, oral	MARALIXIBAT plasma	Homo sapiens
1.44 h	45 mg single, oral	MARALIXIBAT plasma	Homo sapiens
1.97 h	100 mg single, oral	MARALIXIBAT plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
2.7%			MARALIXIBAT plasma	Homo sapiens

Doses

Doses

Show entries

Dose	Population	Adverse events
400 ug/kg/day 1 times / day multiple, oral Highest studied dose	unhealthy, CHILD
400 ug/kg/day 2 times / day multiple, oral Highest studied dose	unhealthy, CHILD

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2,252 inducer 1,087			inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OATP2B1 157 OCTN2 71 BCRP 910 OCTN1 32 OCT3 159 MRP2 499 OATP1B1 1,079	OATP1B3 435 P-gp 2,052 OATP2B1 122 OATP1B1 503 BCRP 697	CYP1A2 832 CYP2B6 669

Drug as perpetrator

Show entries

Target	Modality	Activity	Clinical evidence
CYP1A2 2,333	inducer 1,966	no
CYP2B6 1,160	inducer 1,966	no
CYP3A4 2,633	inducer 1,966	no
OATP2B1 162	inhibitor 4,027	yes [IC50 1.02 uM]	no (co-administration study)
CYP3A4 2,633	inhibitor 4,027	yes [IC50 10.9 uM]	weak (co-administration study)

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Drug as victim

Show entries

Target	Modality	Activity
BCRP 697	substrate 4,014	no
OATP1B1 503	substrate 4,014	no
OATP1B3 435	substrate 4,014	no
OATP2B1 122	substrate 4,014	no
P-gp 2,052	substrate 4,014	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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PubMed

PubMed

Show entries

Title	Date	PubMed
A Drug Regimen for Progressive Familial Cholestasis Type 2.	2018 Jan	29284646
Placebo-Controlled Randomized Trial of an Intestinal Bile Salt Transport Inhibitor for Pruritus in Alagille Syndrome.	2018 Oct	30288474
A Randomized, Controlled, Phase 2 Study of Maralixibat in the Treatment of Itching Associated With Primary Biliary Cholangitis.	2019 Mar	30859149

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Sample Use Guides

In Vivo Use Guide

The recommended dosage is 380 mcg/kg once daily, taken 30 minutes before the first meal of the day.

Route of Administration: Oral

In Vitro Use Guide

In baby hamster kidney cells, maralixibat was shown to be a potent, competitive, and reversible inhibitor of the uptake of [14C]taurocholate by the ASBT (IC50 0.28±0.03nM). Maralixibat also inhibited [14C]alanine uptake via another cellular sodium-dependent cotransporter; however, the potency was markedly lower (IC50 35,700±3000nM). In transfected Chinese hamster ovary cells, maralixibat at 50uM produced a 5% inhibition of liver sodium taurocholate cotransporting polypeptide activity.

Show entries

Name

Type

Language

LOPIXIBAT CHLORIDE

Preferred Name

English

MARALIXIBAT CHLORIDE

Official Name

English

4-AZA-1-AZONIABICYCLO(2.2.2)OCTANE, 1-((4-((4-((4R,5R)-3,3-DIBUTYL-7-(DIMETHYLAMINO)-2,3,4,5-TETRAHYDRO-4-HYDROXY-1,1-DIOXIDO-1-BENZOTHIEPIN-5-YL)PHENOXY)METHYL)PHENYL)METHYL)-, CHLORIDE (1:1)

Systematic Name

English

MARALIXIBAT CHLORIDE [USAN]

Common Name

English

LIVMARLI

Brand Name

English

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Show entries

Classification Tree

Code System

Code

Designated/Withdrawn

FDA ORPHAN DRUG

406213

Positive

EU-Orphan Drug

EU/3/13/1217

Designated/Withdrawn

FDA ORPHAN DRUG

406113

Designated/Approved

FDA ORPHAN DRUG

401513

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Show entries

Code System

Code

Type

Description

SMS_ID

100000181872

PRIMARY

RXCUI

2571073

PRIMARY

EPA CompTox

DTXSID701337104

PRIMARY

ChEMBL

CHEMBL363392

PRIMARY

EVMPD

SUB195693

PRIMARY

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ACTIVE MOIETY


					UYB6UOF69L

Maralixibat

SUBSTANCE RECORD


					V78M04F0XC

MARALIXIBAT CHLORIDE

SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

PubMed

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator