IC50: 8 nM (MTP)[1]
Microsomal triglyceride transfer protein (MTP) [1]
Lomitapide targets microsomal triglyceride transfer protein (MTP), which is essential for the assembly and secretion of apolipoprotein B-containing lipoproteins (VLDL and chylomicrons) in the liver and intestine. By inhibiting MTP, it reduces the production of VLDL and lowers LDL cholesterol levels.

Lomitapide is an oral microsomal triglyceride transfer protein (MTP) inhibitor indicated for the treatment of patients with HoFH, a
rare form of hypercholesterolemia that can lead to premature atherosclerotic disease. Lomitapide undergoes hepatic metabolism viacytochrome P-450 (CYP) isoenzyme 3A4 and interacts with CYP3A4 substrates including atorvastatin and simvastatin[2].

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Lomitapide inhibits MTP with an in vitro IC50 of 8 nM. This potent inhibition prevents the assembly of VLDL particles in the liver, leading to reduced secretion of triglyceride-rich lipoproteins and subsequent lowering of plasma LDL cholesterol levels. The compound's high potency makes it effective at low doses.

The use of lomitapide alone or in combination with other lipid-lowering modalities reduces plasma concentrations of low density lipoprotein cholesterol (LDL-C) by a mean of more than 50%. Lomitapide is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels. The bioavailability of the 50-mg lomitapide capsule is 7.1%. The mean half-life of lomitapide is 39.7 hours[2]. Single-dose administration of lomitapide is shown to reduce serum triglycerides by 35% and 47% at 0.3- and 1-mg/kg doses, respectively. Multiple-dose treatment with lomitapide also results in
dose dependent decrease in triglycerides (71%–87%), nonesterified fattyacids(33%–40%), and LDL-C(26-29%)[3].[1] In a Phase I open-label trial in 6 patients with HoFH (ages 18-40), incremental daily doses of lomitapide (0.03, 0.1, 0.3, and 1.0 mg/kg, each for 4 weeks) reduced mean total cholesterol by 29.8% at 0.3 mg/kg/day (from 851 to 601 mg/dL, p<0.001) and by 58.4% at 1.0 mg/kg/day (p<0.001). Mean LDL-C decreased by 24.7% at 0.3 mg/kg/day (from 614 to 465 mg/dL, p<0.001) and by 50.9% at 1.0 mg/kg/day (p<0.001). Mean triglycerides decreased by 34.1% at 0.3 mg/kg/day (from 283 to 165 mg/dL, p=0.02) and by 65.2% at 1.0 mg/kg/day (p<0.001). In a Phase II randomized, double-blind trial in patients with moderate hypercholesterolemia, lomitapide at escalating doses (5, 7.5, 10 mg daily over 3 months) reduced LDL-C by 19-30% (p=0.013 vs ezetimibe monotherapy). Combination with ezetimibe 10 mg daily reduced LDL-C by 35-46% (p<0.001 vs ezetimibe alone). Total cholesterol, non-HDL-C, and apo B were also significantly reduced. Median Lp(a) was significantly reduced with lomitapide alone or with ezetimibe. HDL-C and apo A-I decreased by 6-9% and 8-11% respectively with lomitapide.
In a Phase III open-label, multicenter trial in 29 HoFH patients (26-week efficacy phase followed by 52-week safety phase), lomitapide added to existing lipid-lowering therapy (including statins, ezetimibe, apheresis) was dosed from 5 mg daily up to 60 mg daily. At week 26, mean LDL-C was reduced by 50% from baseline. Total cholesterol, apo B, triglycerides, and Lp(a) were also significantly reduced. Three patients discontinued apheresis and three others extended intervals between apheresis treatments.
In an unpublished randomized double-blind trial (preliminary data), lomitapide 2.5 mg for 4 weeks then 5 mg daily for 4 weeks plus atorvastatin 20 mg daily reduced LDL-C by 49.9% after 8 weeks, compared to 39% with atorvastatin alone [1].
In vivo, Lomitapide has been shown to significantly reduce LDL cholesterol levels in patients with homozygous familial hypercholesterolemia. The compound is administered orally and has demonstrated efficacy in clinical trials, leading to FDA approval for this indication. It reduces both LDL cholesterol and triglycerides in a dose-dependent manner.

Cell-free MTP assays for Lomitapide utilize purified MTP protein and fluorescent or radiolabeled lipid substrates (triglyceride and phospholipid). The transfer of lipids between donor and acceptor vesicles is measured in the presence of increasing concentrations of the compound. IC50 values are determined from concentration-response curves. The assay can be performed using human or recombinant MTP.

Hepatic cell lines (e.g., HepG2) or primary human hepatocytes are treated with Lomitapide at various concentrations. Secretion of apolipoprotein B-containing lipoproteins into the culture medium is measured by ELISA. Intracellular lipid accumulation is assessed by Oil Red O staining or lipid extraction followed by quantification. Cell viability is monitored to assess cytotoxicity.

In vivo studies for Lomitapide were conducted in animal models (rodents, dogs, monkeys) and in human clinical trials. The compound is administered orally, and plasma lipid levels (total cholesterol, LDL cholesterol, triglycerides) are measured over time. Pharmacodynamic effects on lipoprotein production can be assessed using stable isotope tracer studies. Efficacy in reducing LDL cholesterol has been demonstrated in HoFH patients.

[1] After oral administration of 60 mg lomitapide to healthy volunteers, plasma Cmax was 1.2 ng/mL and AUC was 65 ng·hr/mL, with Tmax of 6 hours. Bioavailability of the 50 mg capsule was 7.1%. Mean half-life was 39.7 hours. When administered with a high-fat meal, Cmax and AUC increased by 77% and 58%, respectively; with a low-fat meal, increases were 70% and 52%, respectively. Lomitapide is highly protein bound (99.8%) and has a steady-state volume of distribution of 985-1292 L. It undergoes significant hepatic metabolism via CYP3A4 to inactive major metabolites M1 and M3. Over 50% of the dose (primarily M1) is excreted in urine, and approximately 35% (mostly parent drug) in feces. Lomitapide is not a P-glycoprotein substrate but inhibits it in vitro.
In patients with mild hepatic impairment (Child-Pugh 5-6), after 60 mg fasting, AUC increased by 47% and Cmax by 4% vs healthy volunteers; in moderate impairment (Child-Pugh 7-9), AUC increased by 164% and Cmax by 361%.
In patients with end-stage renal disease (ESRD), after 60 mg, M1 metabolite AUC and Cmax increased by 200% and 108%, respectively; lomitapide AUC and Cmax increased by 40% and 50% vs healthy volunteers [1].
Lomitapide is orally bioavailable. Following oral administration, it is absorbed and distributed to the liver where it exerts its MTP inhibitory effect. The compound undergoes extensive metabolism, primarily via CYP3A4. PK parameters including Tmax, half-life, clearance, and bioavailability have been characterized in humans. Dose adjustments are required based on concomitant medications and liver function.

[1] Gastrointestinal adverse events: diarrhea, nausea, dyspepsia, vomiting. In Phase I, five of six patients reported increased stool frequency (transient). In Phase II, nine patients (18%) receiving lomitapide developed elevated transaminases leading to discontinuation; levels returned to baseline within two weeks. More patients on lomitapide alone had transaminase elevations than those on combination with ezetimibe. GI symptom severity was greater in lomitapide-only group (p=0.007). In Phase III, 27 of 29 patients reported GI events; three discontinued by week 12. Aminotransferase elevations >3x ULN occurred in 10 patients; >5x ULN in 40% of these. Elevations were managed per protocol and not associated with bilirubin or alkaline phosphatase increases. Hepatic fat increased significantly (to >30% in some cases) but was transient, normalizing 4-14 weeks after.
A boxed warning exists: lomitapide may cause ALT/AST elevations (≥3x ULN observed in trials). Before initiation and monthly or before each dose increase for first year, then every 3 months, monitor transaminases, alkaline phosphatase, total bilirubin. Warning about increased hepatic fat (steatosis) independent of transaminase elevations, which may predispose to cirrhosis. Patients consuming >1 alcoholic drink/day or taking other hepatotoxic drugs require more frequent monitoring. Access is limited under FDA risk evaluation and mitigation strategies program; prescribers and pharmacies must be certified.
Drug interactions: Concomitant use with strong CYP3A4 inhibitor ketoconazole increased lomitapide Cmax and AUC by 15- and 27-fold, respectively, and increased half-life by ~60%; coadministration should be avoided. Moderate CYP3A4 inhibitors also contraindicated. With atorvastatin 20 mg daily, lomitapide 60 mg daily increased atorvastatin acid AUC by 52% and Cmax by 63%. With simvastatin 20 mg daily, lomitapide 10 mg increased simvastatin Cmax by 35% and AUC by 39%; at lomitapide 60 mg with simvastatin 40 mg, Cmax and AUC increased nearly 2-fold. With warfarin, lomitapide 60 mg increased R-warfarin Cmax and AUC by 14% and 28%, and S-warfarin by 15% and 30%, leading to a mean 22% increase in INR.
Contraindications: moderate-to-severe liver disease, sustained abnormal LFTs, strong or moderate CYP3A4 inhibitors, pregnancy [1].
Toxicity of Lomitapide includes hepatotoxicity (elevated liver transaminases, hepatic steatosis) and gastrointestinal effects (diarrhea, nausea, vomiting) due to its mechanism of action. Liver function must be monitored regularly during treatment. The compound is contraindicated in patients with hepatic impairment. Standard genotoxicity, reproductive toxicity, and chronic toxicity studies have been conducted to support regulatory approval.

Am J Health Syst Pharm. 2014 Jun 15;71(12):1001-8.

Lomitabine mesylate is a mesylate prepared from equimolar amounts of lobitapaste and mesylate. It can be used as an adjunct to a low-fat diet and other lipid-lowering therapies in patients with homozygous familial hypercholesterolemia. It has cholesterol-lowering and microsomal triglyceride transfer protein (MTP) inhibitory effects. It contains lobitapaste (1+). Lomitabine mesylate is the mesylate form of lobitapaste, a small molecule inhibitor of microsomal triglyceride transfer protein. See also: Lomitabine (containing the active moiety).

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[1] Lomitapide is a small 9H-fluorenecarboxamide derivative that directly binds to and inhibits MTP within the endoplasmic reticulum lumen of hepatocytes and intestinal enterocytes, thereby inhibiting chylomicron and VLDL synthesis and reducing circulating LDL-C. It was granted FDA approval through the orphan drug program for HoFH. Dosing: initiate at 5 mg once daily, increase to 10 mg after at least 2 weeks, then to 20, 40, and max 60 mg with at least 4 weeks between adjustments. Take without food, at least 2 hours after evening meal, with water. Patients must take daily supplements of vitamin E, linoleic acid, α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid due to reduced absorption of fat-soluble vitamins and fatty acids. In mild hepatic impairment or ESRD, max dose 40 mg daily. With weak CYP3A4 inhibitors (e.g., atorvastatin), max lomitapide dose 30 mg daily. With simvastatin, reduce simvastatin dose by 50%. Estimated yearly cost >$250,000. Place in therapy: for HoFH patients unable to achieve LDL-C goal on high-dose statins or statin-intolerant, or undergoing lipoprotein apheresis to potentially reduce apheresis frequency [1].
Lomitapide mesylate (molecular formula C39H37F6N3O2·xCH4O3S) was approved by the FDA in 2012 for the treatment of homozygous familial hypercholesterolemia. It is marketed under the brand name Juxtapid. The compound is also known as BMS-201038 and AEGR-733. It represents a targeted therapy for this rare genetic disorder.

C39H37F6N3O2.XCH4O3S

789.82604

789.267

202914-84-9

Lomitapide;182431-12-5

11274333

White to off-white solid powder

10.319

3

12

10

55

1200

0

QKVKOFVWUHNEBX-UHFFFAOYSA-N

InChI=1S/C39H37F6N3O2.CH4O3S/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;1-5(2,3)4/h1-6,9-18,28H,7-8,19-25H2,(H,46,50)(H,47,49);1H3,(H,2,3,4)

N-(2,2,2-trifluoroethyl)-9-(4-(4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamido)piperidin-1-yl)butyl)-9H-fluorene-9-carboxamide methanesulfonate

BMS 201038; AEGR733; AEGR-733; BMS-201038; BMS201038; AEGR 733; BMS 201038-01. Lomitapide mesylate. Brand name: Juxtapid; Lojuxta.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~126.61 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.17 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (3.17 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (3.17 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)