Fenofibrate (Page 4 of 7)

12.2 Pharmacodynamics

A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B, an LDL membrane complex, are associated with human atherosclerosis. Similarly, decreased levels of HDL-C and its transport complex, apolipoprotein A (apo AI and apo AII) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C, LDL-C, and TG, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering triglycerides (TG) on the risk of cardiovascular morbidity and mortality has not been determined.

Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides and triglyceride rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL) and apolipoproteins apo AI and apo AII.

12.3 Pharmacokinetics

Plasma concentrations of fenofibric acid after administration of three 48 mg or one 145 mg tablets are equivalent under fed conditions to one 200 mg micronized fenofibrate capsule.

Fenofibrate is a pro-drug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation.

Absorption

The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration.

Exposure to fenofibric acid in plasma, as measured by Cmax and AUC, is not significantly different when a single 145 mg dose of fenofibrate is administered under fasting or nonfasting conditions.

Distribution

Upon multiple dosing of fenofibrate, fenofibric acid steady state is achieved within 9 days. Plasma concentrations of fenofibric acid at steady state are approximately double of those following a single dose. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.

Metabolism

Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma.

Fenofibric acid is 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 indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.

Elimination

After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.

Fenofibric acid is eliminated with a half-life of 20 hours, allowing once daily dosing.

Special Populations

Geriatrics

In elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that a similar dosage regimen can be used in elderly with normal renal function, without increasing accumulation of the drug or metabolites [see DOSAGE AND ADMINISTRATION (2.5) and USE IN SPECIFIC POPULATIONS (8.5)].

Pediatrics

The pharmacokinetics of fenofibrate has not been studied in pediatric populations.

Gender

No pharmacokinetic difference between males and females has been observed for fenofibrate.

Race

The influence of race on the pharmacokinetics of fenofibrate has not been studied, however fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability.

Renal Impairment

The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) showed 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 (eGFR 30 to 59 mL/min/1.73 m2) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of fenofibrate should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment [see DOSAGE AND ADMINISTRATION (2.4)].

Hepatic Impairment

No pharmacokinetic studies have been conducted in patients with hepatic impairment.

Drug-drug Interactions

In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.

Table 2 describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table 3 describes the effects of co-administered fenofibrate or fenofibric acid on other drugs.

Table 2: Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibrate Administration
Co Administered Drug Dosage Regimen of Co Administered Drug Dosage Regimen of Fenofibrate Changes in Fenofibric Acid Exposure
*
Fenofibrate oral tablet
Fenofibrate oral micronized capsule
AUC Cm a x
Lipid lowering agents
Atorvastatin 20 mg once daily for 10 days Fenofibrate 160 mg * once daily for 10 days ↓2% ↓4%
Pravastatin 40 mg as a single dose Fenofibrate 3 x 67 mg as a single dose ↓1% ↓2%
Fluvastatin 40 mg as a single dose Fenofibrate 160 mg * as a single dose ↓2% ↓10%
Anti diabetic agents
Glimepiride 1 mg as a single dose Fenofibrate 145 mg * once daily for 10 days ↑1% ↓1%
Metformin 850 mg three times daily for 10 days Fenofibrate 54 mg * three times daily for 10 days ↓9% ↓6%
Rosiglitazone 8 mg once daily for 5 days Fenofibrate 145 mg * once daily for 14 days ↑10% ↑3%
Table 3: Effects of Fenofibrate Co-Administration on Systemic Exposure of Other Drugs
Dosage Regimen of Fenofibrate Dosage Regimen of Co Administered Drug Changes in Co Administered Drug Exposure
*
Fenofibrate oral tablet
Fenofibrate oral micronized capsule
Analyte AUC Cm a x
Lipid lowering agents
Fenofibrate 160 mg * once daily for 10 days Atorvastatin, 20 mg once daily for 10 days Atorvastatin ↓17% 0%
Fenofibrate 3 x 67 mg as a single dose Pravastatin, 40 mg as a single dose Pravastatin3α-Hydroxyl-iso-pravastatin ↑13%↑26% ↑13%↑29%
Fenofibrate 160 mg * as a single dose Fluvastatin, 40 mg as a single dose (+)-3R, 5S-Fluvastatin ↑15% ↑16%
Anti diabetic agents
Fenofibrate 145 mg * once daily for 10 days Glimepiride, 1 mg as a single dose Glimepiride ↑35% ↑18%
Fenofibrate 54 mg * three times daily for 10 days Metformin, 850 mg three times daily for 10 days Metformin ↑3% ↑6%
Fenofibrate 145 mg * once daily for 14 days Rosiglitazone, 8 mg once daily for 5 days Rosiglitazone ↑6% ↓1%

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