Homozygous familial hypercholesterolaemia (HoFH) is characterised by markedly elevated low-density lipoprotein cholesterol (LDL-C) levels and increased cardiovascular disease burden. Currently available lipid-lowering drugs and apheresis have significantly improved the prognosis for patients with HoFH. But most patients with the disease still have LDL-C levels far above the target level of <2.5 mmol/L, and will experience progressive atherosclerosis and cardiovascular complications. Recent research has focussed on investigating other mechanisms of lowering LDL-C levels in HoFH patients. In this paper, we will describe a potent microsomal triglyceride-transfer protein (MTP) inhibitor for HoFH research–Lomitapide.
Lomitapide is a potent inhibitor of MTP with an IC50 of 8 nM in vitro.
Lomitapide (AEGR-733; BMS-201038) can reduce plasma levels of LDL-C by inhibiting the activity of MTP in the liver and the intestine. Thereby it inhibits the synthesis of VLDL and chylomicrons. Now, it has received regulatory approval in the European Union, the United States of America, Canada and Mexico for use under a restricted program as add-on treatment in patients with HoFH.
In Vitro: First of all, Lomitapide is an oral MTP inhibitor for the treatment of patients with HoFH. Secondly, it undergoes hepatic metabolism via cytochrome P-450 (CYP) isoenzyme 3A4 and interacts with CYP3A4 substrates including Atorvastatin and Simvastatin.
In Vivo: Lomitapide is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels. Firstly, 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%. Secondly, the bioavailability of the 50-mg lomitapide capsule is 7.1%. The mean half-life of lomitapide is 39.7 hours. Moreover, Lomitapide (single-dose) shows to reduce serum triglycerides by 35% and 47% at 0.3- and 1-mg/kg doses, respectively. Furthermore, multiple-dose treatment with lomitapide also results in dose dependent decrease in triglycerides (71%–87%), nonesterified fattyacids(33%–40%), and LDL-C(26-29%).
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