Drugs Xagena
Lomitapide ( Lojuxta [ EU ], Juxtapid [ US ] ) lowers cholesterol through a different pathway, i.e. through the inhibition of the microsomal triglyceride transfer protein ( MTP ).
MTP is involved in the loading of triglyceride onto apolipoprotein B100, which is part of the assembly process of very-low density lipoprotein ( VLDL ). After excretion by hepatocytes, VLDL is converted to LDL. By blocking the assembly of VLDL, Lomitapide reduces VLDL release and VLDL-mediated triglyceride secretion. This leads to a reduction of LDL levels in plasma.
Lomitapide has been approved by both the FDA ( Food and Drug Administration ) and EMA ( European Medicines Agency ) for the treatment of adult HoFH patients as adjunct to a low fat diet and other lipid-lowering therapies, with or without LDL
Apheresis.
In three clinical trials, Lomitapide lowered plasma LDL levels effectively by up to 51% compared to baseline values. Lomitapide treatment is started with a daily oral dose of 5 mg, taken two or more hours after the evening meal. The dose may be gradually increased after two weeks, based upon tolerability and response, up to a maximum daily dose of 60 mg.
Lomitapide is both a substrate and inhibitor for CYP3A4 metabolism. Co-administration with moderate to strong inhibitors of CYP3A4 is therefore contraindicated.
The regular monitoring of hepatic function can mitigate the risks posed by Lomitapide’s hepatic effects.
Gastrointestinal side effects are very common in patients treated with Lomitapide, with an incidence of about 90%. Diarrhea, nausea, dyspepsia and vomiting were reported in over 30% of the patients, while pain, discomfort and bloating of the abdomen, constipation and flatulence were observed less frequently ( ± 20% ).
Elevated liver aminotransferase levels are a serious side effect reported in 10 out of 29 patients in a phase 3 trial. The frequency and severity of these adverse reactions are reduced when patients are on a low fat diet.
The inhibition of VLDL-mediated triglyceride secretion can lead to hepatic accumulation of triglycerides. ( Xagena )
Goulooze SC et al, Br J Clin Pharmacol 2015; Epub ahead of print
XagenaMedicine_2015
