Identification

Name
Lomitapide
Accession Number
DB08827
Type
Small Molecule
Groups
Approved, Investigational
Description

Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor used in homozygous familial hypercholesterolemia (HoFH) patients. It is marketed under the name Juxtapid (R).

Structure
Thumb
Synonyms
  • AEGR 733
  • BMS 201038
  • lomitapida
External IDs
AEGR-733 / AEGR-773 / BMS 201038 / BMS-201038-01 / BMS-201038-04
Product Ingredients
IngredientUNIICASInChI Key
Lomitapide mesylateX4S83CP54E202914-84-9QKVKOFVWUHNEBX-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
JuxtapidCapsule5 mg/1OralAegerion Pharmaceuticals2013-01-03Not applicableUs
JuxtapidCapsule5 mgOralAegerion Pharmaceuticals2014-05-06Not applicableCanada
JuxtapidCapsule60 mg/1OralAegerion Pharmaceuticals2013-01-03Not applicableUs
JuxtapidCapsule20 mg/1OralAegerion Pharmaceuticals2013-01-03Not applicableUs
JuxtapidCapsule20 mgOralAegerion Pharmaceuticals2014-05-06Not applicableCanada
JuxtapidCapsule40 mg/1OralAegerion Pharmaceuticals2013-01-03Not applicableUs
JuxtapidCapsule10 mg/1OralAegerion Pharmaceuticals2013-01-03Not applicableUs
JuxtapidCapsule10 mgOralAegerion Pharmaceuticals2014-05-06Not applicableCanada
JuxtapidCapsule30 mg/1OralAegerion Pharmaceuticals2013-01-03Not applicableUs
International/Other Brands
Lojuxta
Categories
UNII
82KUB0583F
CAS number
182431-12-5
Weight
Average: 693.7204
Monoisotopic: 693.278996673
Chemical Formula
C39H37F6N3O2
InChI Key
MBBCVAKAJPKAKM-UHFFFAOYSA-N
InChI
InChI=1S/C39H37F6N3O2/c40-38(41,42)25-46-36(50)37(33-13-5-3-10-30(33)31-11-4-6-14-34(31)37)21-7-8-22-48-23-19-28(20-24-48)47-35(49)32-12-2-1-9-29(32)26-15-17-27(18-16-26)39(43,44)45/h1-6,9-18,28H,7-8,19-25H2,(H,46,50)(H,47,49)
IUPAC Name
N-(2,2,2-trifluoroethyl)-9-[4-(4-{2-[4-(trifluoromethyl)phenyl]benzamido}piperidin-1-yl)butyl]-9H-fluorene-9-carboxamide
SMILES
FC(F)(F)CNC(=O)C1(CCCCN2CCC(CC2)NC(=O)C2=C(C=CC=C2)C2=CC=C(C=C2)C(F)(F)F)C2=CC=CC=C2C2=CC=CC=C12

Pharmacology

Indication

Used in homozygous familial hypercholesterolemia (HoFH) patients to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-HDL-C).

Associated Conditions
Pharmacodynamics

Lomitapide directly inhibits microsomal triglyceride transfer protein (MTP).

Mechanism of action

Within the lumen of the endoplasmic reticulum, lomitapide inhibits microsomal triglyceride transfer protein (MTP), which prevents the formation of apolipoprotein B, and, thus, the formation of VLDL and chylomicrons as well. Altogether, this leads to a reduction of low-density lipoprotein cholesterol.

TargetActionsOrganism
AMicrosomal triglyceride transfer protein large subunit
antagonist
Human
Absorption

In healthy patients, time to maximum lomitapide concentration is about 6 hours with a single dose of 60 mg. Lomitapide has an approximate absolute bioavailability of 7%.

Volume of distribution

The steady state volume of distribution is about 985-1292 L.

Protein binding

Plasma protein binding is about 99.8%

Metabolism

Lomitapide is mainly metabolized by CYP3A4 to it's inactive metabolites, M1 and M3. CYP enzymes that metabolize lomitapide to a minor extent include CYP 1A2,2B6,2C8,2C19.

Route of elimination

About 52.9-59.5% is eliminated by the urine and 33.4-35.1% is eliminated by the feces.

Half life

Lomitapide half-life is about 39.7 hours.

Clearance
Not Available
Toxicity

Contra-indicated in pregnancy, and moderate to severe hepatic insufficiency (Child-Pugh category B or C). Severe GI adverse reactions may occur.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Lomitapide can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of Lomitapide can be decreased when combined with (S)-Warfarin.
3,5-diiodothyropropionic acidThe metabolism of Lomitapide can be decreased when combined with 3,5-diiodothyropropionic acid.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Lomitapide.
5-androstenedioneThe metabolism of Lomitapide can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Lomitapide can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of Lomitapide can be decreased when combined with 6-O-benzylguanine.
AbemaciclibThe metabolism of Lomitapide can be decreased when combined with Abemaciclib.
AbirateroneThe metabolism of Lomitapide can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Lomitapide can be decreased when combined with Acalabrutinib.
Food Interactions
  • Avoid grapefruit juice, which will likely increase lomitapide plasma concentrations.
  • When taking lomitapide with food, the risk of GI side effects is increased.

References

General References
  1. Cuchel M, Meagher EA, du Toit Theron H, Blom DJ, Marais AD, Hegele RA, Averna MR, Sirtori CR, Shah PK, Gaudet D, Stefanutti C, Vigna GB, Du Plessis AM, Propert KJ, Sasiela WJ, Bloedon LT, Rader DJ: Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013 Jan 5;381(9860):40-6. doi: 10.1016/S0140-6736(12)61731-0. Epub 2012 Nov 2. [PubMed:23122768]
  2. Cuchel M, Bloedon LT, Szapary PO, Kolansky DM, Wolfe ML, Sarkis A, Millar JS, Ikewaki K, Siegelman ES, Gregg RE, Rader DJ: Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med. 2007 Jan 11;356(2):148-56. [PubMed:17215532]
External Links
KEGG Drug
D09637
PubChem Compound
9853053
PubChem Substance
175427108
ChemSpider
8028764
BindingDB
50098320
ChEBI
72297
ChEMBL
CHEMBL354541
PharmGKB
PA166114922
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Lomitapide
ATC Codes
C10AX12 — Lomitapide
AHFS Codes
  • 24:06.92 — Miscellaneous Antilipemic Agents
FDA label
Download (930 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableEffect of Atorvastatin on the Pharmacokinetics of Lomitapide1
1CompletedNot AvailableHealthy Volunteers1
1CompletedNot AvailableIntra-subject Variability of Pharmacokinetics1
1CompletedOtherHealthy Volunteers1
1CompletedTreatmentHealthy Volunteers1
2CompletedTreatmentHigh Cholesterol3
2CompletedTreatmentHomozygous Familial Hypercholesterolemia1
2CompletedTreatmentHyperlipidemias1
3CompletedTreatmentDyslipidemia (Fredrickson Type Ⅱa)1
3CompletedTreatmentFamilial Hypercholesterolemia - Homozygous1
3CompletedTreatmentHomozygous Familial Hypercholesterolemia1
3WithdrawnTreatmentHomozygous Familial Hypercholesterolemia1
Not AvailableEnrolling by InvitationNot AvailableHomozygous Familial Hypercholesterolemia1
Not AvailableEnrolling by InvitationNot AvailablePregnancy1
Not AvailableWithdrawnNot AvailableHomozygous Familial Hypercholesterolemia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral10 mg
CapsuleOral10 mg/1
CapsuleOral20 mg/1
CapsuleOral20 mg
CapsuleOral30 mg/1
CapsuleOral40 mg/1
CapsuleOral5 mg
CapsuleOral5 mg/1
CapsuleOral60 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5739135No2012-12-122015-04-14Us
US5712279No1996-02-212016-02-21Us
US6492365No1999-12-102019-12-10Us
US8618135No2005-03-072025-03-07Us
US7932268No2007-08-192027-08-19Us
US9265758No2005-03-072025-03-07Us
US9433617No2005-03-072025-03-07Us
US9364470No2005-03-072025-03-07Us
US9861622No2005-03-072025-03-07Us
US10016404No2005-03-072025-03-07Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
logP7.7ChemAxon
pKa (Strongest Acidic)10.35ChemAxon
pKa (Strongest Basic)9.02ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area61.44 Å2ChemAxon
Rotatable Bond Count12ChemAxon
Refractivity181.73 m3·mol-1ChemAxon
Polarizability68.08 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
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/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as fluorenes. These are compounds containing a fluorene moiety, which consists of two benzene rings connected through either a cyclopentane, cyclopentene, or cyclopenta-1,3-diene.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Fluorenes
Sub Class
Not Available
Direct Parent
Fluorenes
Alternative Parents
Biphenyls and derivatives / Trifluoromethylbenzenes / Benzamides / Benzoyl derivatives / Aralkylamines / Piperidines / Fatty amides / Amino acids and derivatives / Secondary carboxylic acid amides / Trialkylamines
show 7 more
Substituents
Fluorene / Biphenyl / Trifluoromethylbenzene / Benzamide / Benzoic acid or derivatives / Benzoyl / Aralkylamine / Monocyclic benzene moiety / Fatty amide / Piperidine
show 23 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
piperidines, benzamides, fluorenes, (trifluoromethyl)benzenes (CHEBI:72297)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Protein heterodimerization activity
Specific Function
Catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid between phospholipid surfaces (PubMed:23475612, PubMed:8939939, PubMed:26224785, PubMed:25108285, PubMed:22236406). Requ...
Gene Name
MTTP
Uniprot ID
P55157
Uniprot Name
Microsomal triglyceride transfer protein large subunit
Molecular Weight
99350.255 Da

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
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

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
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

Drug created on January 03, 2013 13:34 / Updated on November 14, 2018 12:55