New Drug Approvals 2012 - Pt. XXXI - Lomitapide (JuxtapidTM)

ATC Code: C10AX12
Wikipedia: Lomitapide

On December 21^st, the FDA approved Lomitapide (Tradename: Juxtapid; Research Codes: BMS-201038-04, BMS-201038, AEGR-733), a Microsomal triglyceride transfer protein (MTP) inhibitor, as a complement to a low-fat diet and other lipid-lowering treatments, in patients with homozygous familial hypercholesterolemia (HoFH).

Familial hypercholesterolemia is a genetic disorder, characterised by high levels of cholesterol rich low-density lipoproteins (LDL-C) in the blood. This genetic condition is generally attributed to a faulty mutation in the LDL receptor (LDLR) gene, which mediates the endocytosis of LDL-C.

Lomitapide, trough the inhibition of the microsomal triglyceride transfer protein in the liver, prevents the assembly of Apoliprotein B-containing lipoproteins, which is required for the formation of LDLs, thus contributing to lower the circulating LDL-C levels.

The Microsomal triglyceride transfer protein, which resides in the lumen of the endoplasmic reticulum, is a heterodimer composed of the microsomal triglyceride transfer protein large subunit (Uniprot: P55157; ChEMBL: CHEMBL2569), and the protein disulfide isomerase. Lomitapide binds to the large subunit.

>MTP_HUMAN Microsomal triglyceride transfer protein large subunit
MILLAVLFLCFISSYSASVKGHTTGLSLNNDRLYKLTYSTEVLLDRGKGKLQDSVGYRIS
SNVDVALLWRNPDGDDDQLIQITMKDVNVENVNQQRGEKSIFKGKSPSKIMGKENLEALQ
RPTLLHLIHGKVKEFYSYQNEAVAIENIKRGLASLFQTQLSSGTTNEVDISGNCKVTYQA
HQDKVIKIKALDSCKIARSGFTTPNQVLGVSSKATSVTTYKIEDSFVIAVLAEETHNFGL
NFLQTIKGKIVSKQKLELKTTEAGPRLMSGKQAAAIIKAVDSKYTAIPIVGQVFQSHCKG
CPSLSELWRSTRKYLQPDNLSKAEAVRNFLAFIQHLRTAKKEEILQILKMENKEVLPQLV
DAVTSAQTSDSLEAILDFLDFKSDSSIILQERFLYACGFASHPNEELLRALISKFKGSIG
SSDIRETVMIITGTLVRKLCQNEGCKLKAVVEAKKLILGGLEKAEKKEDTRMYLLALKNA
LLPEGIPSLLKYAEAGEGPISHLATTALQRYDLPFITDEVKKTLNRIYHQNRKVHEKTVR
TAAAAIILNNNPSYMDVKNILLSIGELPQEMNKYMLAIVQDILRFEMPASKIVRRVLKEM
VAHNYDRFSRSGSSSAYTGYIERSPRSASTYSLDILYSGSGILRRSNLNIFQYIGKAGLH
GSQVVIEAQGLEALIAATPDEGEENLDSYAGMSAILFDVQLRPVTFFNGYSDLMSKMLSA
SGDPISVVKGLILLIDHSQELQLQSGLKANIEVQGGLAIDISGAMEFSLWYRESKTRVKN
RVTVVITTDITVDSSFVKAGLETSTETEAGLEFISTVQFSQYPFLVCMQMDKDEAPFRQF
EKKYERLSTGRGYVSQKRKESVLAGCEFPLHQENSEMCKVVFAPQPDSTSSGWF

There are no known 3D structures for this protein.

Lomitapide (IUPAC: N-(2,2,2-trifluoroethyl)-9-{4-[4-({[4'-(trifluoromethyl)biphenyl-2- yl]carbonyl}amino)piperidin-1-yl]butyl}-9H-fluorene-9-carboxamide; Canonical smiles: FC(F)(F)CNC(=O)C1(CCCCN2CCC(CC2)NC(=O)c3ccccc3c4ccc(cc4)C(F)(F)F)c5ccccc5c6ccccc16; PubChem: 9853053; Chemspider: 8028764 ; ChEMBL: CHEMBL354541; Standard InChI Key: MBBCVAKAJPKAKM-UHFFFAOYSA-N) is a synthetic compound with a molecular weight of 693.7 Da, nine hydrogen bond acceptors, two hydrogen bond donors, and has an ALogP of 7.79. The compound is therefore not compliant with the rule of five.

Lomitapide is available in the capsular form and the recommended starting daily dose is 5mg, with the possibility to gradually increase it, based on acceptable safety and tolerability, up to a maximum of 60mg. It has an apparent volume of distribution of 985-1292 L, upon oral administration of a single 60-mg dose, and its absolute bioavailability is 7%. Lomitapide binds extensively to plasma proteins (99.8%). The mean terminal half-life (t_1/2) of lomitapide is 39.7 hours, being mainly metabolised by CYP3A4. This reliance on CYP3A4 for metabolism leads to multiple opportunities for drug-drug interactions with both CYP3A4 inhibitors and inducers, therefore when combining lomitapide with other lipid-lowering therapies, i.e. statins, a dose adjustment is required.

Lomitapide has been given a black box warning due to an increase in transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) levels after exposure to the drug.

The license holder for Juxtapid^TM is Aegerion Pharmaceuticals, and the full prescribing information can be found here.