Lomitapide

Uses

Lomitapide is a microsomal triglyceride transfer protein inhibitor used to lower cholesterol associated with homozygous familial hypercholesterolemia (HoFH), reducing risk of cardiovascular events such as myocardial infarction and stroke.

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).

Lomitapide is also used to associated treatment for these conditions: Homozygous Familial Hypercholesterolemia

How Lomitapide works

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.

Toxicity

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

Food Interaction

• Avoid grapefruit products.
• Take with food. Food decreases the risk of GI side effects.

[Major] ADJUST DOSING INTERVAL: Administration of lomitapide with food may increase the risk of common gastrointestinal adverse reactions such as diarrhea, nausea, vomiting, dyspepsia, abdominal pain or discomfort, abdominal distension, constipation, and flatulence.

Absorption of concomitant oral medications may be affected in patients who develop diarrhea or vomiting.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of lomitapide.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

Weak CYP450 3A4 inhibitors can increase lomitapide exposure (AUC) by approximately 2-fold according to the product labeling.

Ketoconazole, a potent CYP450 3A4 inhibitor, has been shown to increase lomitapide AUC by 27-fold .

GENERALLY AVOID: Coadministration with alcohol may increase the risk of hepatotoxicity associated with the use of lomitapide.

In a premarketing clinical trial, 34% (10<29) of patients treated with lomitapide had at least one elevation in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 3 times the upper limit of normal (ULN) or greater, and 14% (4<29) had at least one elevation in ALT or AST 5 times ULN or greater.

There were no concomitant clinically meaningful elevations of total bilirubin, international normalized ratio (INR), or alkaline phosphatase.

Lomitapide also increases hepatic fat, with or without concomitant increases in transaminases.

In the same study, the median absolute increase in hepatic fat was 6% after both 26 and 78 weeks of treatment, from 1% at baseline, measured by magnetic resonance spectroscopy.

Hepatic steatosis associated with lomitapide may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis.

Clinical data suggest that hepatic fat accumulation is reversible after stopping treatment with lomitapide, although the long-term consequences are unknown.

MANAGEMENT: Lomitapide should be taken once daily with a glass of water, without food, at least 2 hours after the evening meal.

Strict adherence to a low-fat diet (

Lomitapide Drug Interaction

Major: divalproex sodiumModerate: fexofenadineUnknown: mupirocin topical, diphenhydramine, dicyclomine, bisacodyl, buspirone, sucralfate, benzoic acid / methenamine / sodium salicylate, docusate/senna, amitriptyline, pentosan polysulfate sodium, estradiol topical, immune globulin subcutaneous, sumatriptan, levetiracetam, clonazepam, levocarnitine, lamotrigine, mesalamine

Lomitapide Disease Interaction

Major: liver impairmentModerate: alcohol, galactosemia, renal impairment, vitamin deficiency

Volume of Distribution

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

Elimination Route

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%.

Half Life

Lomitapide half-life is about 39.7 hours.

Elimination Route

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

Innovators Monograph

You find simplified version here Lomitapide