Lomitapide

Introduction

Lomitapide is an expensive orphan drug approved for use only in patients with homozygous familial hypercholesterolemia (HoFH). Higher rates of hepatoxicity additionally limit its use in other clinical populations.

Clinical Highlight I

• Due to risk of serious hepatoxicity, cost and tolerability issues, lomitapide should only be considered for patients with HoFH.

Appropriate Uses

Low-density lipoprotein (LDL-C) Lowering

The Food and Drug Administration (FDA) has approved lomitapide for use only in patients with HoFH as an adjunct to lipid-lowering medications, LDL apheresis and diet to reduce low-density lipoprotein cholesterol (LDL-C), apoB, total cholesterol, and non–high-density lipoprotein cholesterol (HDL-C). The safety of lomitapide in patients without HoFH has not been established.

ASCVD Event Reduction

No cardiovascular outcomes trials have been performed or are planned for lomitapide.

Mechanism of Action

Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor. Lomitapide directly binds MTP in the lumen of the endoplasmic reticulum, preventing assembly of apoB-containing lipoproteins in the hepatocyte (apoB-100 → very low-density lipoprotein (VLDL)) and the enterocyte (apoB-48 → chylomicrons) (Figure 29-1). Reduced synthesis of VLDL decreases levels of the downstream metabolites intermediate-density lipoprotein (IDL), LDL and likely lipoprotein (a) (Lp(a)).

Patients taking lomitapide have impaired absorption of dietary fat and fat soluble vitamins, along with reduced transportation of vitamin E from the liver to the periphery. Due to impaired fat absorption, patients have oral fat intolerance. In the liver, decreased utilization of triglyceride in VLDL synthesis can result in fat accumulation.

Lomitapide undergoes extensive metabolism in the liver through a variety of pathways including CYP3A4 and glucuronidation. Lomitapide is excreted in the feces and the major metabolite in the urine.

Enlarge 

Dosing

• LFTs—Measure alanine aminotransferase (SGPT) (ALT), aspartate transaminase (SGOT) (AST), total bilirubin and alkaline phosphatase at baseline.
• Low fat diet—Initiate a low fat diet with <20% of energy from fat.
• Lomitapide—Start with 5 mg daily. Increase dose based on acceptable safety and tolerability: increase to 10 mg after 2 weeks, then at a minimum of 4-week intervals to 20 mg, 40 mg, up to the maximum recommended dose of 60 mg daily (Table 29-1).
• Take once daily with water and without food, at least 2 hours after the evening meal to reduce gastrointestinal adverse effects.
• Adjust dosing based on concomitant CYP3A4 inhibitor use, renal impairment, or baseline hepatic impairment (Table 29-2). The dose should not exceed 40 mg daily for patients with stable, mild hepatic impairment (Child-Pugh A) with a known cause.
• Vitamins—Lomitapide can reduce the absorption of fat-soluble vitamins/fatty acids in the small intestine. Start vitamin E 400 IU, linoleic acid 200 mg, alpha-linoleic acid(ALA) 210 mg, docosahexaenoic acid (DHA) 80 mg and eicosapentaenoic acid (EPA) 110 mg as supplements.

Enlarge 

Enlarge 

Efficacy

Lomitapide has been evaluated in patients with functional HoFH defined as one or more of:

• Genetic testing confirming two mutant alleles in the LDL receptor gene
• Skin fibroblast LDL receptor activity <20% normal
• Untreated total cholesterol >500 mg/dL and triglycerides <300 mg/dL and both parents with total cholesterol >250 mg/dL prior to lipid-lowering therapy.

In patients with HoFH on a low fat diet and stable lipid-lowering therapy including apheresis, after 26 weeks of therapy lomitapide reduced LDL-C by 40% from baseline (Figure 29-2), with similar reductions in total cholesterol, apoB, and non–HDL-C. Triglycerides were reduced by 45%, with no effect on HDL-C.

Enlarge 

Contraindications

• Pregnancy
• Concomitant use with a strong or moderate CYP3A4 inhibitor
• Moderate or severe hepatic impairment, active liver disease, or unexplained persistent transaminase elevations

Safety

Pregnancy and Nursing Mothers

Lomitapide may cause fetal harm based on teratogenicity studies in animals. Women with reproductive potential should have a negative pregnancy test before starting lomitapide and use effective contraception during treatment. The maximum dose of lomitapide in women receiving oral contraceptives is 30 mg daily.

Nursing mothers should discontinue lomitapide or discontinue nursing.

Hepatotoxicity

Black Box Warning – Hepatoxicity

Because of the risk of hepatotoxicity, lomitapide is available only through the restricted Juxtapid REMS Program.

Lomitapide can cause elevations in transaminases and/or hepatic fat. Hepatic steatosis is a risk factor for progressive liver disease, including steatohepatitis and cirrhosis.

• Measure ALT, ASK, alkaline phosphatase and total bilirubin before initiating treatment and then every 3 months during the first year and every 6 months thereafter.
• During treatment, adjust the dose of lomitapide if the ALT or AST is ≥3 times the upper limit of normal (ULN).
• Discontinue for clinically significant liver toxicity.

In the lomitapide HoFH trial, 34% of patients experienced at least one ALT or AST elevation ≥3 times upper limit of normal (ULN) and 14% had at least one ALT or AST elevation ≥5 times ULN. Bilirubin, alkaline phosphatase and international normalized ratio (INR) were not elevated. During a 78-week HoFH trial, no patients discontinued lomitapide due to hepatic transaminase elevations. During the open-label extension, two of 19 patients experienced persistent ALT elevations despite dose reductions.

Lomitapide also increases hepatic fat, with or without transaminase elevations. Absolute hepatic fat increased by a median of 6% after 26 and 78 weeks of lomitapide treatment from a baseline of 1% on magnetic resonance imaging (MRI). Hepatic fat accumulation is reversible after stopping lomitapide treatment, but the histologic sequelae are unknown with long-term use. One case study of a patient receiving 12 years of lomitapide for recurrent hypertriglyceridemic pancreatitis reported progression of fatty liver to steatohepatitis and fibrosis.

Monitoring

ALT and AST should be measured prior to each dose increase or monthly, whichever comes first. After the first year, measure ALT and AST every 3 months or before a dose increase.

Dose Adjustment

The dose of lomitapide should be reduced or discontinued based on transaminase elevations (Table 29-2). Lomitapide should be discontinued if transaminase elevations are accompanied by symptoms of liver injury, including jaundice, nausea, vomiting, abdominal pain, fever, lethargy, flu-like symptoms, increased bilirubin ≥2 times ULN, or active liver disease. The etiology should be investigated.

Enlarge 

Gastrointestinal

Adverse gastrointestinal effects occurred in 93% of patients taking lomitapide, including diarrhea (79%), nausea (65%), vomiting (34%), dyspepsia (38%) and abdominal pain or flatulence (20%). Severe gastrointestinal reactions were reported by 21% of patients and were the cause of drug discontinuation in 14% of patients. A low fat diet with <20% calories from fat and gradual dose increases may reduce the risk of gastrointestinal effects.

Renal

End-stage renal disease receiving dialysis should receive a maximum dose of lomitapide 40 mg daily.

Decreased Fat Soluble Nutrient Absorption

The mechanism of action of lomitapide in the intestine may reduce absorption of fat soluble nutrients. See Dosing section for recommended supplementation.

Drug-Drug Interactions

CYP3A4 Inhibitors

Strong and moderate inhibitors of CYP3A4 increase exposure to lomitapide and are contraindicated. Avoid grapefruit juice.

Do not exceed lomitapide 30 mg when using with weak CYP3A4 inhibitors, including atorvastatin, simvastatin, lovastatin, oral contraceptives, alprazolam, amiodarone, amlodipine, bicalutamide, cilostazol, cimetidine, cyclosporine, fluoxetine, fluvoxamine, ginkgo, goldenseal, isoniazid, lapatinib, nilotinib, pazopanib, ranitidine, ranolazine, tipranavir/ritonavir, ticagrelor, zileuton. Reduce the dose of simvastatin and lovastatin by 50% when coadministered with lomitapide due to increased risk of myopathy.

Hepatoxicity

Avoid concomitant use of lomitapide with other potential hepatotoxins, including acetaminophen (>4 g per day for ≥3 days per week), amiodarone, isotretinoin, methotrexate, tetracyclines and tamoxifen.

Fat Soluble Drugs, Vitamins and Fatty Acids

Lomitapide may reduce absorption.

Warfarin

Lomitapide increased blood levels of warfarin. Monitor INR levels regularly, especially after lomitapide dose adjustment.

P-glycoprotein (P-gp) Substrates

Consider dose reduction of P-gp substrate because lomitapide may increase absorption.

Bile Acid Sequestrants

Separate dosing by at least 4 hours.