Fenofibrate

Fenofibrate is an enhanced sustained/quick-release tablet formulation of the PPAR alpha agonist fenofibrate formulated with the company's MeltDose technology. It Is through PPAR activation that fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma. The resulting fall in triglycerides produces an alteration in the size and composition of LDL. Activation of PPARa also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol.

Fenofibrate is specifically indicated as an adjunctive therapy to diet for the treatment of hyperlipidemia, mixed dyslipidemia and hypertriglyceridemia.

Fenofibrate is supplied in 40 mg and 120 mg tablets designed for oral administration. The recommended initial dose of the drug for hyperlipidemia and mixed dyslipidemia is is 120 mg per day. The recommended initial dose for hypertriglyceridemia is 40 to 120 mg per day. The maximum dose is 120 mg per day.

FDA Approval
FDA approval of Fenofibrate was based on the results of six clinical trials.

Hyperlipidemia and Mixed Dyslipidemia
Four randomized, placebo-controlled, double-blind, parallel group studies evaluated the effects of Fenofibrate administered at a dose of 120 mg per day. In the pooled cohorts, the mean baseline values were: total-C 306.9 mg/dL; LDL-C 213.8 mg/dL; HDL-C 52.3 mg/dL; and triglycerides 191.0 mg/dL. Fenofibrate resulted in the following mean changes: total-C (-18.7%), LDL-C (-20.6%), HDL-C (+11.0%), and triglycerides (-28.9%) versus -0.4%, -2.2%, +0.7% and +7.7%, respectively, for placebo (p=<0.05).

Hypertriglyceridemia
Two randomized, double-blind, placebo controlled trials enrolled 147 subjects who received Fenofibrate at doses of 120 mg per day for eight weeks.
Study One
This trial enrolled subjects with mean baseline triglyceride levels of 350 to 499 mg/dL. Fenofibrate primarily decreased triglycerides, from a mean baseline value of 432 to a mean endpoint value of 223, a -46.2% mean change; very low density lipoprotein (VLDL) triglycerides from a mean baseline value of 350 to a mean endpoint value of 178, a -44.1% change and VLDL Cholesterol from a mean baseline value of 92 to a mean endpoint value of 46, a -44.7% change (p<0.05 versus placebo).
Study Two
This trial enrolled subjects with mean baseline triglyceride levels of 500 to 1500 mg/dL. Fenofibrate primarily decreased triglycerides from a mean baseline value of 726 to a mean endpoint value of 308, a -54.5% change; VLDL triglycerides from a mean baseline value of 543 to a mean endpoint value of 205, a -50.6% change and VLDL cholesterol from a mean baseline value of 126 to a mean endpoint value of 54, a -49.4% change (p<0.05 versus placebo).

Adverse events associated with the use of Fenofibrate may include, but are not limited to, the following:

• Abnormal Liver Tests
• Respiratory Disorder
• Abdominal Pain
• Back Pain
• Increased AST

Fenofibrate activates the peroxisome proliferator activated receptor a (PPARa). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARa also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol.

van der Hoogt CC, de Haan W, Westerterp M, Hoekstra M, Dallinga-Thie GM, Romijn JA, Princen HM, Jukema JW, Havekes LM, Rensen PC Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression. Journal of Lipid Research 2007 Aug;48(8):1763-71

Hiukka A, Leinonen E, Jauhiainen M, Sundvall J, Ehnholm C, Keech AC, Taskinen MR Long-term effects of fenofibrate on VLDL and HDL subspecies in participants with type 2 diabetes mellitus. Diabetologia 2007 Jul 26

Lai CQ, Arnett DK, Corella D, Straka RJ, Tsai MY, Peacock JM, Adiconis X, Parnell LD, Hixson JE, Province MA, Ordovas JM. Fenofibrate effect on triglyceride and postprandial response of apolipoprotein A5 variants: the GOLDN study. Arteriosclerosis, Thrombosis, and Vascular Biology 2007 Jun;27(6):1417-25.

Keating GM, Croom KF Fenofibrate: a review of its use in primary dyslipidaemia, the metabolic syndrome and type 2 diabetes mellitus. Drugs 2007;67(1):121-53.

Scott R, Best J, Forder P, Taskinen MR, Simes J, Barter P, Keech A; FIELD Study Investigators Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study: baseline characteristics and short-term effects of fenofibrate [ISRCTN64783481]. Cardiovascular Diabetology 2005 Aug 22;4:13

Ko HS, Kim CJ, Ryu WS Effect of fenofibrate on lipoprotein(a) in hypertriglyceridemic patients: impact of change in triglyceride level and liver function. Journal of Cardiovascular Pharmacology 2005 Oct;46(4):405-11

Sommariva D, Bonfiglioli D, Pogliaghi I, Ottomano C, Fasoli A Fenofibrate therapy of hypertriglyceridaemia. Differential effects on LDL cholesterol level in type IV and in type IIb primary hyperlipoproteinaemia. European Journal of Clinical Pharmacology 1984;26(6):741-4.