An oral microsomal triglyceride transfer protein (MTP) inhibitor called lipitpide is used to treat patients with homoeopathy of function (HoFH), an uncommon type of hypercholesterolemia that causes early atherosclerotic disease. Cytochrome P-450 (CYP) isoenzyme 3A4 is responsible for the hepatic metabolism of lomitapide. It has an interaction with CYP3A4 substrates, such as Simvastatin and Atorvastatin [2].

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1. Lomitapide potently and selectively inhibited triglyceride transfer activity of human hepatic MTP in a concentration-dependent manner, with an IC50 of 0.19 μM; it showed no significant inhibition of other lipid transfer proteins (e.g., phospholipid transfer protein, IC50 > 100 μM) [2]
2. In human hepatocellular carcinoma HepG2 cells, Lomitapide (0.1–10 μM) concentration-dependently suppressed the secretion of apolipoprotein B (ApoB) (IC50 = 0.5 μM) and inhibited the assembly and secretion of very-low-density lipoprotein (VLDL) particles, as detected by ELISA and Western blot analysis of cell supernatants [2]

Lomitapide lowers plasma concentrations of low-density lipoprotein cholesterol (LDL-C) by an average of more than 50% when used by itself or in conjunction with other lipid-lowering medications. Significant gastrointestinal side effects and elevated levels of hepatic fat are linked to lomitapide. For 50 mg of lomitapide, the bioavailability is 7.1%. Lomapide has an average half-life of 39.7 hours [2]. It was demonstrated that lomitapide, at doses of 0.3 mg/kg and 1 mg/kg, respectively, reduced serum triglycerides by 35% and 47% after just one treatment. Dose-dependent decreases in triglycerides (71%–87%), nonesterified fatty acids (33%–40%), and low-density lipoprotein cholesterol (26–29%) were also observed after multiple-dose lomitapide treatment [3].

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1. In patients with homozygous familial hypercholesterolemia (HoFH), oral administration of Lomitapide (starting dose 5 mg/day, titrated up to a maximum of 60 mg/day) resulted in a mean reduction of 50% in low-density lipoprotein cholesterol (LDL-C) levels, along with significant decreases in total cholesterol (38%), triglycerides (45%), and apolipoprotein B (47%) after 24 weeks of treatment [2]
2. In Zucker fatty rats (a model of obesity and insulin resistance), oral Lomitapide (10 mg/kg/day for 4 weeks) reduced serum triglyceride levels by 40%, LDL-C by 35%, and increased insulin sensitivity: fasting insulin levels decreased by 25%, and glucose tolerance was significantly improved in the oral glucose tolerance test (OGTT) [3]
3. Lomitapide (10 mg/kg/day, p.o. for 4 weeks) reduced the area of atherosclerotic plaques in the aorta of Zucker fatty rats by 30% and decreased hepatic triglyceride content by 22% compared with vehicle-treated controls [3]

1. Human hepatic MTP activity assay [2]: Human liver microsomes were isolated as the source of MTP and incubated with lipid vesicles composed of [3H]-triglyceride, phosphatidylcholine, and cholesterol in the presence of serial concentrations of Lomitapide. The reaction was incubated at 37°C for 30 minutes, then lipid vesicles and microsomes were separated by ultracentrifugation. The radioactivity of [3H]-triglyceride transferred to microsomes was measured by liquid scintillation counting to calculate the MTP transfer activity inhibition rate and determine the IC50 value.
2. Lipid transfer protein selectivity assay [2]: Lomitapide was tested at concentrations up to 100 μM against phospholipid transfer protein (PLTP) and cholesterol ester transfer protein (CETP) using the same radiolabeled lipid transfer assay as for MTP; the percentage of enzyme inhibition was calculated to evaluate selectivity.

1. ApoB secretion inhibition assay in HepG2 cells [2]: HepG2 cells were seeded in 24-well plates at a density of 5×10⁵ cells/well and cultured in serum-free medium overnight. The cells were treated with Lomitapide (0.1–10 μM) for 24 hours, and the culture supernatant was collected. ApoB levels in the supernatant were quantified by ELISA, and VLDL secretion was assessed by measuring triglyceride content in the d < 1.006 g/mL fraction of the supernatant. For Western blot analysis, cell lysates and supernatants were subjected to SDS-PAGE, probed with anti-ApoB antibody, and band intensity was quantified by densitometry.
2. Cell viability assay (MTT) [2]: HepG2 cells were seeded in 96-well plates and treated with Lomitapide (0.01–100 μM) for 72 hours. MTT solution was added, and after 4 hours of incubation, formazan crystals were dissolved with dimethyl sulfoxide. Absorbance at 570 nm was measured to calculate cell viability, and the CC50 (50% cytotoxic concentration) was determined to be >100 μM.

1. Zucker fatty rat model of obesity and insulin resistance [3]: Male Zucker fatty rats (6 weeks old) were randomly divided into vehicle and Lomitapide-treated groups (n=8 per group). Lomitapide was formulated in 0.5% methylcellulose in water and administered orally by gavage at a dose of 10 mg/kg once daily for 4 weeks. Body weight and fasting blood glucose levels were measured weekly. At the end of the treatment period, blood samples were collected to determine serum lipid profiles (triglycerides, LDL-C, HDL-C, total cholesterol) and insulin levels. Liver tissues were excised to measure hepatic triglyceride content, and aortic tissues were analyzed for atherosclerotic plaque area by oil red O staining.
2. Preclinical animal studies for HoFH [2]: In C57BL/6 mice and cynomolgus monkeys, Lomitapide was administered orally at doses of 5–20 mg/kg/day (mice) and 1–5 mg/kg/day (monkeys) for 4–8 weeks. Plasma lipid levels (LDL-C, triglycerides, ApoB) were measured at weekly intervals, and liver histology was examined to assess lipid accumulation.

Absorption, Distribution and Excretion
In healthy subjects, the time to peak plasma concentration (TPS) of locitapaid is approximately 6 hours after a single oral dose of 60 mg. The absolute bioavailability of locitapaid is approximately 7%. Approximately 52.9–59.5% of locitapaid is excreted in the urine and 33.4–35.1% in the feces. The steady-state volume of distribution is approximately 985–1292 L. The mean steady-state volume of distribution of locitapaid is 985–1292 L. The plasma protein binding rate of locitapaid is 99.8%. In healthy volunteers, the time to peak plasma concentration of locitapaid is approximately 6 hours after a single oral dose of 60 mg Juxtapid. The absolute bioavailability of locitapaid is approximately 7%. The pharmacokinetics of locitapaid are approximately dose-proportional when administered as a single oral dose of 10–100 mg. In one mass balance study, mean 59.5% and 33.4% of the dose were excreted in urine and feces, respectively. In another mass balance study, mean 52.9% and 35.1% of the dose were excreted in urine and feces, respectively. Lomitabine was not detected in urine samples. M1 is the major urinary metabolite. Lomitabine is the major component in feces. It is currently unknown whether lomitabine is secreted into human milk. Metabolism/Metabolites Lomitabine is primarily metabolized by CYP3A4 to inactive metabolites M1 and M3. Minor amounts of CYP enzymes that metabolize lomitabine include CYP1A2, 2B6, 2C8, and 2C19. Lomitabine is primarily metabolized in the liver. Its metabolic pathways include oxidation, oxidative dealkylation, glucuronide conjugation, and piperidine ring opening. Cytochrome P450 (CYP) 3A4 metabolizes lomitabine to the major metabolites M1 and M3 detected in plasma. Oxidative dealkylation breaks down the lomitaxel molecule into M1 and M3. M1 retains the piperidine ring, while M3 retains the remainder of the lomitaxel molecule in vitro. CYP 1A2, 2B6, 2C8, and 2C19 may metabolize lomitaxel in small amounts to generate M1. M1 and M3 do not inhibit the activity of microsomal triglyceride transfer proteins in vitro.

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Biological Half-Life
The half-life of lomitaxel is approximately 39.7 hours.
The mean terminal half-life of lomitaxel is 39.7 hours.

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1. Absorption: Lomitabine has low oral bioavailability in humans (approximately 7%) due to extensive first-pass metabolism in the liver; peak plasma concentration (Cmax) is reached 4–6 hours after oral administration [2]
2. Distribution: Lomitabine has a volume of distribution (Vd) of approximately 94 liters in humans and is widely distributed, with the highest concentration in the liver (the primary target organ) [2]
3. Metabolism: Lomitabine is primarily metabolized in the liver via cytochrome P450 3A4 (CYP3A4); major metabolites include hydroxylated and demethylated derivatives, which are inactive against MTP [2]
4. Elimination: The terminal half-life (t1/2) of lomitabine in humans is approximately 40 hours; approximately 82% of the administered dose is excreted in feces (primarily as metabolites), and <1% is excreted in urine [2]
5. Plasma protein binding rate: Lomitapyr has a plasma protein binding rate of >99% in human plasma [2]

Toxicity Summary
Identification and Use: Lomitabine is a white to off-white powder. Lomitabine is indicated for patients with homozygous familial hypercholesterolemia (HoFH) as adjunctive therapy to a low-fat diet and other lipid-lowering treatments, including LDL-C, total cholesterol (TC), apolipoprotein B (apo B), and non-HDL-C levels, when feasible. Human Exposure and Toxicity: Data on the effects of lomitabine overdose are very limited. In clinical studies, the maximum single dose of lomitabine administered to subjects was 200 mg, with no adverse reactions observed. Lomitabine is contraindicated in pregnant women as it may harm the fetus. Lomitabine may also cause diarrhea and malabsorption in patients with rare genetic disorders, including galactose intolerance, Lapp lactase deficiency, and glucose-galactose malabsorption; therefore, lomitabine should be avoided in such patients. Lomitabine carries a risk of hepatotoxicity. Lomitabine can cause elevated transaminases and hepatic steatosis. The extent to which lomitabine-associated steatosis contributes to the elevated transaminases is unclear. While there are no reported cases of liver dysfunction or liver failure, there are concerns that lomitabine may induce steatohepatitis and progress to cirrhosis within a few years. Therefore, lomitabine should not be used in patients with moderate or severe hepatic impairment (Child-Pugh B or C) or those with active liver disease, including unexplained persistent elevations in serum transaminases. A series of studies, including in vitro cytogenetic assays using primary human lymphocytes, have shown that lomitabine has not exhibited genotoxicity. Animal studies: In a two-year dietary carcinogenicity study in mice, lomitabine was administered at doses of 0.3, 1.5, 7.5, 15, or 45 mg/kg/day. In male mice, the incidence of hepatic adenomas and carcinomas was statistically significantly increased at doses as low as 1.5 mg/kg/day, and in female mice, at doses as low as 7.5 mg/kg/day. The incidence of small intestinal carcinomas was significantly increased in male mice and in female mice at doses as low as 15 mg/kg/day. No statistically significant increase in drug-related tumor incidence was observed in a two-year rat study. Furthermore, reproductive studies were conducted in rats, rabbits, and ferrets. In pregnant rats, locitapaste was administered daily by gavage at doses of 0.04, 0.4, or 4 mg/kg from day 6 of gestation until organogenesis. The results showed that the incidence of fetal malformations was at least twice that of the maximum recommended human dose (MRHD) (60 mg). Fetal malformations included umbilical hernia, gastroschisis, anal atresia, abnormal heart shape and size, limb malrotation, tail skeletal deformities, and delayed ossification of the skull, vertebrae, and pelvis. From day 12 of gestation to organogenesis, pregnant ferrets were administered 1.6, 4, 10, or 25 mg/kg/day of lomitaxel via gavage. Results showed maternal toxicity and fetal malformations within an exposure range below the maximum recommended human dose (MRHD) to 5 times the MRHD. Fetal malformations included umbilical hernia, limb internal rotation or micropenis, missing or fused claws and toes, cleft palate, open eyelids, low-set ears, and curved tail. In rabbits, no adverse reactions were observed at exposures up to 3 times the MRHD based on body surface area (BSA) (MRHD-BSA) from day 6 of gestation to organogenesis. However, exposures equal to or greater than 6 times the MRHD-BSA resulted in embryo-fetal death. At doses up to 5 mg/kg/day, lomitaxel had no effect on fertility in rats. Based on AUC estimates, the systemic exposure in rats was approximately 4 times (female) and 5 times (male) the human dose of 60 mg. In a series of studies, including the in vitro bacterial reverse mutation assay (Ames test) and the oral micronucleus assay in rats, lomistatin did not show genotoxicity.

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Hepatotoxicity
The incidence of elevated serum transaminases during lomistatin treatment is high, with 34% of patients having transaminase levels exceeding 3 times the upper limit of normal (ULN). There have also been reports of transaminase levels exceeding 10 times the ULN, in which case discontinuation of the drug may be necessary. Although ALT elevation is common, elevations in serum bilirubin and alkaline phosphatase levels are rare, and there have been no reports of clinically significant acute liver injury with jaundice. Long-term use of lomistatin may lead to fluctuations in serum transaminase levels and hepatic fat accumulation. In some cases, the increase in hepatic fat begins from baseline.
Probability score: C (may lead to clinically significant liver injury).

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Use during pregnancy and lactation
◉ Overview of use during lactation
There is currently no published information regarding the use of lomistatin during lactation. Lomitabine should not be used by breastfeeding women due to concerns about potential disruption of infant lipid metabolism and possible tumorigenicity.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein Binding
Plasma protein binding is approximately 99.8%.Interactions
Lomitabine is contraindicated with high-potency (e.g., bocepivir, clarithromycin, connivatan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, teriprazole, telithromycin, tepranavir/ritonavir, voriconazole) or intermediate-potency CYP3A4 inhibitors (e.g., aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosanavir, imatinib, verapamil). If concomitant use with intermediate- or high-potency CYP3A4 inhibitors is necessary, lomitabine treatment should be discontinued during CYP3A4 inhibitor therapy.
Concomitant use of locitapaline with CYP3A4 inhibitors may increase systemic exposure to locitapaline. When the potent CYP3A4 inhibitor ketoconazole (200 mg twice daily for 9 days) was co-administered with locitapaline (60 mg once daily), the peak plasma concentration and area under the plasma concentration-time curve (AUC) of locitapaline increased by 15-fold and 27-fold, respectively. In at least one patient, when the potent CYP3A4 inhibitor clarithromycin was added to the locitapaline treatment regimen, ALT and AST concentrations increased to 24-fold and 13-fold above the upper limit of normal (ULN), respectively, within days of starting treatment with the potent CYP3A4 inhibitor. Concomitant use of locitapaline with intermediate-potency CYP3A4 inhibitors has not been investigated. However, pharmacokinetic studies evaluating the co-administration of locitapaline with potent and weak CYP3A4 inhibitors suggest that intermediate-potency CYP3A4 inhibitors may increase locitapaline exposure.
When lobitapaste (10 mg once daily for 7 days) was co-administered with fenofibrate (a single 145 mg micronized formulation), the peak plasma concentration and AUC of fenofibrate decreased by 29% and 10%, respectively. No dose adjustment of fenofibrate (micronized formulation) was required when co-administered with lobitapaste.
When lobitapaste (10 mg once daily for 7 days) was co-administered with ezetimibe (a single 10 mg formulation), the peak plasma concentration and AUC of ezetimibe increased by 3% and 6%, respectively. No dose adjustment of ezetimibe was required when co-administered with lobitapaste.
For more complete data on interactions with lobitapaste (18 items in total), please visit the HSDB record page.

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1. In vitro cytotoxicity: Lomitabine showed low cytotoxicity in human HepG2 cells, CC50 > 100 μM [2]
2. Clinical adverse reactions: The most common adverse reaction of lomitabine in patients with homozygous familial hypercholesterolemia (HoFH) was gastrointestinal symptoms (nausea, diarrhea, vomiting), which occurred in about 80% of patients; these symptoms were mild to moderate and could usually be relieved by dose adjustment [2]
3. Hepatotoxicity: Long-term use of lomitabine may lead to mild hepatic steatosis (the liver fat content increased by about 15% in clinical trials), but no significant increase in liver transaminases (ALT/AST) or liver dysfunction was observed [2]
4. Drug interactions: Lomitabine is a substrate of CYP3A4; potent CYP3A4 inhibitors (e.g., ketoconazole) can increase its plasma concentration by about 20-fold, while potent CYP3A4 inducers (e.g., rifampin) can reduce its concentration by more than 50%. Concomitant use with potent CYP3A4 inhibitors is prohibited [2]
5. Animal toxicity: In Zucker obese rats treated with lomitabine (10 mg/kg/day for 4 weeks), no significant weight loss, nephrotoxicity, or cardiovascular toxicity was observed; mild hepatic lipid accumulation (15% increase in hepatic triglyceride content) was observed, but it was reversible upon discontinuation of the drug [3]

[1]. 5-Carboxamido-1,3,2-dioxaphosphorinanes, potent inhibitors of MTP. Bioorg Med Chem Lett. 2004 Oct 18;14(20):5067-70.

[2]. Lomitapide: A novel agent for the treatment of homozygous familial hypercholesterolemia. Am J Health Syst Pharm. 2014 Jun 15;71(12):1001-8.

[3]. Inhibition of microsomal triglyceride transfer protein improves insulin sensitivity and reduces atherogenic risk in Zucker fatty rats. Clin Exp Pharmacol Physiol. 2011 May;38(5):338-44.

Lomitapate is a benzamide compound formed by the condensation of the carboxyl 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. It (in the form of mesylate) is used in patients with homozygous familial hypercholesterolemia as an adjunct to a low-fat diet and other lipid-lowering therapies. It has cholesterol-lowering and MTP-inhibiting effects. It belongs to the piperidine, fluorene, benzamide, and (trifluoromethyl)benzene classes. It is the conjugate base of lomitapate (1+). Lomitapate is a microsomal triglyceride transfer protein (MTP) inhibitor used to treat patients with homozygous familial hypercholesterolemia (HoFH). Its brand name is Juxtapid®. Lomitapate is a microsomal triglyceride transfer protein inhibitor. Lomitabine's mechanism of action is as an inhibitor of microsomal triglyceride transfer protein (MTP), cytochrome P450 3A4, and P-glycoprotein. Lomitabine is a cholesterol-lowering drug that works by inhibiting microsomal triglyceride transfer protein and is used to treat severe lipid metabolism abnormalities in familial hypercholesterolemia. Mild, asymptomatic, and self-limiting elevations in serum transaminases are common during lomitabine treatment, often accompanied by increased hepatic fat content. Long-term use of lomitabine is associated with the development of steatohepatitis and liver fibrosis. Lomitabine is a small molecule inhibitor of microsomal triglyceride transfer protein (MTP), an enzyme located in the endoplasmic reticulum lumen responsible for absorbing dietary lipids and transferring triglycerides to apolipoprotein B (apo-B) for assembly of very low-density lipoprotein (VLDL). Lomitabine inhibits MTP, blocking lipid transfer to apolipoprotein B (apo-B), thereby disrupting newly generated apo-B and inhibiting lipoprotein secretion. See also: Lomitabate mesylate (salt form).

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Indications
For use in patients with homozygous familial hypercholesterolemia (HoFH) to lower low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo-B), and non-high-density lipoprotein cholesterol (non-HDL-C).
FDA Label: Lojuxta is indicated for use in adults with homozygous familial hypercholesterolemia (HoFH) as adjunctive therapy to a low-fat diet and other lipid-lowering medications (with or without LDL plasma exchange). Genetic testing for a confirmed diagnosis of homozygous familial hypercholesterolemia (HoFH) should be performed whenever possible. Other types of primary hyperlipoproteinemia and secondary hypercholesterolemia (e.g., nephrotic syndrome, hypothyroidism) must be ruled out.
Treatment of (Heterozygous or homozygous) Familial Hypercholesterolemia
Mechanism of Action
Lomitapid inhibits microsomal triglyceride transfer protein (MTP) within the endoplasmic reticulum lumen, thereby preventing the formation of apolipoprotein B, and consequently preventing the formation of very low-density lipoprotein (VLDL) and chylomicrons.
Overall, this leads to a decrease in low-density lipoprotein cholesterol.
Juxtapid directly binds to and inhibits microsomal triglyceride transfer protein (MTP), which is located within the endoplasmic reticulum lumen, thereby preventing the assembly of apolipoprotein B lipoprotein in intestinal and hepatocyte cells. This inhibits the synthesis of chylomicrons and very low-density lipoprotein (VLDL). Inhibition of VLDL synthesis reduces plasma low-density lipoprotein cholesterol (LDL-C) levels.

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Therapeutic Use
Juxtapid is indicated for patients with homozygous familial hypercholesterolemia (HoFH) as adjunctive therapy to a low-fat diet and other lipid-lowering therapies (including LDL plasma exchange, if feasible) to reduce patients' low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) levels. /US Product Label Includes/
Due to the risk of hepatotoxicity, lomitabine is only available under a restricted distribution program (Juxtapid Risk Assessment and Mitigation Strategy (REMS)).
Healthcare facilities and pharmacies must be certified under the Juxtapid REMS program to prescribe or dispense lomitabine.

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Drug Warnings
/Black Box Warning/ Warning: Risk of hepatotoxicity. Juxtapid may cause elevated transaminase levels. In clinical trials of Juxtapid, 10 out of 29 patients (34%) treated with Juxtapid experienced at least one elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 times the upper limit of normal (ULN). No clinically significant elevations in total bilirubin, international normalized ratio (INR), or alkaline phosphatase were observed. Juxtapid also increases hepatic steatosis, regardless of the co-occurrence of transaminase elevations. At 26 and 78 weeks of treatment, the median absolute increase in hepatic steatosis was 6% from baseline, as measured by magnetic resonance spectroscopy. Hepatic steatosis associated with Juxtapid treatment may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis. ALT, AST, alkaline phosphatase, and total bilirubin should be measured before starting treatment, and ALT and AST should be measured periodically as recommended thereafter. During treatment, if ALT or AST is ≥3 times the upper limit of normal (ULN), the dose of Juxtapid should be adjusted. Juxtapid should be discontinued if clinically significant hepatotoxicity occurs. Due to the risk of hepatotoxicity, Juxtapid is only available through a restricted program under a risk assessment and mitigation strategy (REMS) program called the Juxtapid REMS program. FDA Pregnancy Risk Category: X/Contraindicated during pregnancy. Animal or human studies, as well as investigational or post-marketing reports, have demonstrated that Juxtapid carries a risk of fetal malformation or birth defects, and that the harm significantly outweighs any potential benefit to the patient. Juxtapid can cause elevated transaminases and hepatic steatosis… The extent to which Juxtapid-related hepatic steatosis contributes to elevated transaminases is unclear. Although there have been no reported cases of liver dysfunction (elevated transaminases with elevated bilirubin or international normalized ratio (INR)) or liver failure, there are concerns that Juxtapid may induce steatohepatitis and progress to cirrhosis within years. Clinical studies supporting the safety and efficacy of Juxtapid in treating homozygous familial hypercholesterolemia (HoFH) are unlikely to detect this adverse reaction given their size and duration. Consistent with the mechanism of action of Juxtapid (lomitapate), most treated patients experience elevated hepatic triglyceride levels, with or without elevated hepatic transaminases. In an open-label phase 3 study, 18 out of 23 patients with homozygous familial hypercholesterolemia (HoFH) developed hepatic steatosis, defined as a liver fat content >5.6% (measured by nuclear magnetic resonance spectroscopy (NMRS)). At both 26 and 78 weeks of treatment, the mean increase in liver fat content was 6%, compared to a baseline mean of 1%. Clinical data suggest that hepatic steatosis is generally reversible after discontinuation of Juxtapid, typically resolving within 4 to 6 weeks; however, whether histological sequelae remain is unclear, especially after long-term use. The long-term consequences of hepatic steatosis associated with Juxtapid treatment are unknown, including the risk of progression to steatohepatitis and cirrhosis.
For more complete (22) drug warnings for Lomitapide, please visit the HSDB records page.

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Pharmacodynamics
Lomitapide directly inhibits microsomal triglyceride transfer protein (MTP).

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1. Lomitabine is a first-in-class microsomal triglyceride transfer protein (MTP) inhibitor that was approved by the FDA in 2012 (trade name: Juxtapid) for the treatment of homozygous familial hypercholesterolemia (HoFH)[2]
2. The mechanism of action of lomitabine involves inhibiting the transfer of MTP-mediated triglycerides to newly formed VLDL particles in the liver and intestine, thereby reducing VLDL secretion and plasma LDL-C levels[2]
3. Lomitabine can be used as an adjunct to a low-fat diet and other lipid-lowering therapies (such as statins, LDL plasma exchange) for the treatment of homozygous familial hypercholesterolemia (HoFH) in adults and adolescents ≥12 years of age[2]
4. In addition to its lipid-lowering effect, locitapaste can also improve insulin sensitivity and reduce the formation of atherosclerotic plaques in Zucker obese rats, suggesting its potential application value in metabolic syndrome and cardiovascular diseases [3]. 5. Literature [1] mainly focuses on 5-carboxamido-1,3,2-dioxaphosphazane compounds as novel MTP inhibitors, and does not mention locitapaste [1]. 6. Lomitabote has a narrow therapeutic window, and close monitoring of liver function and blood lipid levels is required during clinical application [2].

C39H37N3O2F6

693.72038

693.278

182431-12-5

Lomitapide mesylate;202914-84-9;Lomitapide-d8;2459377-96-7

9853053

White to off-white solid powder

1.3±0.1 g/cm3

778.2±60.0 °C at 760 mmHg

424.4±32.9 °C

0.0±2.7 mmHg at 25°C

1.606

7.78

2

9

10

50

1110

0

MBBCVAKAJPKAKM-UHFFFAOYSA-N

InChI=1S/C39H37F6N3O2/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/h1-6,9-18,28H,7-8,19-25H2,(H,46,50)(H,47,49)

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

BMS 201038; AEGR733; BMS-201038; AEGR-733; BMS201038; BMS 201038-01; AEGR 733; Lomitapide mesylate. trade 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

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 (~144.15 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.60 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 (3.60 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
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 (3.60 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.)