Lomitapide

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%.

Toxicity

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

Description

Lomitapide was approved by the US FDA in December 2012 for the treatment of patients with familial hypercholesteremia (referred to as HoFH) in conjunction with a low-fat diet andother lipid-lowering treatments. Lomitapide was discovered from a high-through put screen that identified several structurally distinct MTP inhibitors. Combination of key structural features from two structurally distinct HTS hits provided potent MTP inhibitors. Parallel analog synthesis led to lomitapide as an optimized structure. Lomitapide was synthesized via alkylation of 9-fluorenylcarboxylic acid with 1,4-dibromobutane which, after trifluoroethylamide formation, provided a bromide intermediate that was displaced by Boc-4-aminopiperidine. Introduction of the 4'-trifluoromethylbiphenylcarboxamide gave lomitapide, which was found to inhibit MTP with an IC₅₀ of 0.5 nM and to exhibit good cholesterol-lowering efficacy in Sprague–Dawley rats (intravenous and oral ED₅₀～0.2 mg/kg).

Description

The drug lomitapide was originally developed to reduce low-density lipids (“bad” cholesterol) but failed in Phase I clinical trials.?M. Beer and colleagues at Aegerion Pharmaceuticals (Cambridge, MA), however, “rescued” lomitapide?by developing it as a treatment for the orphan disease homozygous familial hypercholesterolemia (HoFH), a genetic disorder that affects the liver and often causes heart failure. Lomitapide inhibits the microsomal triglyceride transfer protein needed for the assembly of bad cholesterol and its secretion in the liver. Aegerion and its pharmaceutical services partner, Aptuit (Greenwich, CT), rushed lomitapide through trials; and the US FDA approved as an HoFH drug.

Originator

Bristol-Myers Squibb (United States)

The Uses of Lomitapide

Lomitapide has been used as a microsomal triglyceride transfer protein (MTP) inhibitor to study its effects on very-low-density lipoproteins (VLDL) export in mouse hepatocytes.

Indications

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).

Background

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

Definition

ChEBI: Lomitapide is a member of the class of benzamides obtained by formal condensation of the carboxy group of 4'-(trifluoromethyl)biphenyl-2-carboxylic acid with the primary amino group of 9-[4-(4-aminopiperidin-1-yl)butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide. Used (as its mesylate salt) as a complement to a low-fat diet and other lipid-lowering treatments in patients with homozygous familial hypercholesterolemia. It has a role as an anticholesteremic drug and a MTP inhibitor. It is a member of piperidines, a member of fluorenes, a member of benzamides and a member of (trifluoromethyl)benzenes. It is a conjugate base of a lomitapide(1+).

brand name

Juxtapid

Biochem/physiol Actions

Lomitapide is an inhibitor of microsomal triglyceride transfer protein (MTP). Lomitapide has been shown to be highly effective in reducing LDL-cholesterol and triglycerides, and has been aproved for treatment of homozygous familial hypercholesterolemia.

Pharmacokinetics

Lomitapide directly inhibits microsomal triglyceride transfer protein (MTP).

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.