Trilipix Mechanism of Action

Pharmacotherapeutic Group: Serum lipid-reducing agents, cholesterol and triglycerides reducers, fibrates. ATC Code: C10AB.
Pharmacology: Pharmacodynamics: The active moiety of Trilipix is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate.
The lipid-modifying effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptorα (PPARα). Through this mechanism, fenofibric acid increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of Apo CIII (an inhibitor of lipoprotein lipase activity).
The resulting decrease in tryglycerides 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 PPARα also induces an increase in the synthesis of HDL-C and Apo AI and AII.
Elevated levels of Total-C, LDL-C and Apo B and decreased levels of HDL-C and its transport complex, Apo AI and Apo AII are risk factors for human atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the levels of Total-C, LDL-C and triglycerides and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering triglycerides on the risk of cardiovascular morbidity and mortality has not been determined.
Pharmacokinetics: Trilipix contains fenofibric acid, which is the only circulating pharmacologically active moiety in plasma after oral administration of Trilipix. Fenofibric acid is also the circulating pharmacologically active moiety in plasma after oral administration of fenofibrate, the ester of fenofibric acid.
Plasma concentrations of fenofibric acid after administration of 1 Trilipix 135 mg delayed-release capsule are equivalent to those after one 200 mg capsule of micronized fenofibrate administered under fed conditions.
Absorption: Fenofibric acid is well-absorbed throughout the gastrointestinal tract. The absolute bioavailabilty of fenofibric acid is approximately 81%.
Peak plasma levels of fenofibric acid occur within 4-5 hrs after single dose administration of Trilipix capsule under fasting conditions.
Fenofibric acid exposure in plasma, as measured by maximum peak concentrations (C_max) and area under the curve (AUC), is not significantly different when a single Trilipix 135 mg dose is administered under fasting or non-fasting conditions.
Distribution: Upon multiple dosing of Trilipix, fenofibric acid levels reach steady state within 8 days. Plasma concentrations of fenofibric acid at steady state are approximately slightly more than double those following a single dose. Serum protein-binding is approximately 99% in normal and dyslipidemic subjects.
Metabolism: Fenofibric acid primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine.
In vivo metabolism data after fenofibrate administration indicate that fenofibric acid does not undergo oxidative metabolism (eg, cytochrome P450) to a significant extent.
Excretion: After absorption, Trilipix is primarily excreted in the urine in the form of fenofibric acid and fenofibric acid glucuronide.
Fenofibric acid is eliminated with a half-life (t_½) of approximately 20 hrs, allowing once-daily administration of Trilipix.
Special Populations: Geriatrics: In 5 elderly volunteers 77-87 years, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/hr, which compared to 1.1 L/hr in young adults. This indicates that an equivalent dose of Trilipix can be used in elderly subjects with normal renal function, without increasing accumulation of the drug or metabolites.
Renal Impairment: The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate and severe renal impairment. Patients with severe renal impairment [creatinine clearance (CrCl) <30 mL/min] showed a 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. Patients with mild to moderate renal impairment (CrCl 30-80 mL/min) had similar exposure but an increase in the t_½ for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of Trilipix should be avoided in patients who have severe renal impairment and dose reduction in patients having mild to moderate renal impairment.
Toxicology: Fenofibric Acid: Because fenofibrate is rapidly converted to its active metabolite, fenofibric acid, either during or immediately following absorption both in animals and humans, studies conducted with fenofibrate are relevant for the assessment of the toxicity profile of fenofibric acid. The systemic toxicity of fenofibrate and fenofibric acid in animal studies is comparable.
Fenofibrate: Chronic toxicity studies have yielded no relevant information about specific toxicity of fenofibrate. Studies on mutagenicity of fenofibrate have been negative.
In rats and mice, liver tumours have been found at high doses, which are attributable to peroxisome proliferation. These changes are specific to small rodents and have not been observed in other animal species. This is of no relevance to therapeutic use in man.
Studies in mice, rats and rabbits did not reveal any teratogenic effect. Embryonic effects were observed at doses in the range of maternal toxicity. Prolongation of the gestation period and difficulties during delivery were observed at high doses. No sign of any effect on fertility has been detected.