Fenofibrate Ezetimibe

Currently, there are a number of systemic and intestine-selective MTP inhibitors, including lomitapide (23, BMS-201038, AEGR-733), implitapide (24), JTT-130, SLx-4090, and R-256918 (latter three structures not disclosed) believed to be in active development [60]. In a meta-analysis of three Phase II clinical trials, lomitapide as monotherapy or in combination with ezetimibe, atorvastatin, or fenofibrate significantly reduced LDL cholesterol (up to 35% as monotherapy and 66% in combination with atorvastatin) and was well tolerated with less than 2% discontinuation due to abnormal liver function [61]. Lomitapide has also been granted orphan drug status for the treatment of homozygous familial hypercholesterolemia [59]. Results of a Phase II study of JTT-130 for type 2 diabetes are expected in August 2010 [59,60]. 

Co-administration of ezetimibe and fenofibrate in 32 healthy subjects with hypercholesterolemia (6) resulted in no significant changes in laboratory test results, including enzymes indicative of muscle or liver injury. 

Kosoglou T, Statkevich P, Fruchart JC, Pember LJ, Reyderman L, Cutler DL, Guillaume M, Maxwell SE, Veltri EP. Pharmacodynamic and pharmacokinetic interaction between fenofibrate and ezetimibe. Curr Med Res Opin 2004 20(8) 1197-207. 

Abbreviations AM, amlodipine AT, atorvastatin DS, diclofenac sodium EZ, ezetimibe FB, fenofibrate HAT, hydroxy atorvastatin IS, internal standard o-HAT, ortfio-hydroxy atorvastatin p-HAT, para-hydroxy atorvastatin HPLC-ESI-MS, high-performance liquid chromatography with electrospray tandem mass spectrometry LV, lovastatin NA, nicotinic acid NB, novobiocin FV, pravastatin RV, rosuastatin SV, simvastatin RT, roxethromycin UPLC, ultra performance liquid chromatography. 

Gustavson LE, Schweitzer SM, Burt Achari R, Rieser MJ, Hdeld T, Chira T, Yannicelli HD, Kelly MT. Evaluatioii of the potential for phannacokinetic interaction between fenofibrate and ezetimibe a phase 1, open-label, mult le-dose, three-period crossover study in healthy subjects. Clin Ther (200 28,373—87. 

The authors of a major review of rosuvastatin concluded that its adverse reaction profile resembles that of other commonly used statins [34 ]. Increments in fiver enzymes are in most cases minor and of minimal concern, renal dysfunction is quite uncommon, myopathy is unusual, and rhab-domyolysis is rare. Interactions with other drugs are fisted but no new information given. Combinations with fenofibrate, omega-3 fatty acids, ezetimibe, rifampicin, and clopidogrel appear to be safe. 

In dislipilemic coronary patients with claudication, combination therapy with simvastatin 40 mg and ezetimibe (149) 10 mg (trade name of the combination preparation Vytorin) after dinner combined with fenofibrate (Tricor) 160 mg (94) with breakfast brings a significant improvement in walking time to onset of claudication, and time to absolute claudication (see Chapter 1) measured on the treadmill (personal observations). There is also a remarkable improvement of the patient s lipid profile with this combination therapy. 

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