FIBRICOR (Page 4 of 7)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The active moiety of FIBRICOR 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 receptor α (PPARα). Through this mechanism, fenofibric acid 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 decrease in TG produces an alteration in the size and composition of LDL from small, dense particles 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 apoproteins A-I, A-II and HDL-cholesterol.

Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.

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

Absorption

The absolute bioavailability of FIBRICOR has not been determined as the compound is virtually insoluble in aqueous media suitable for injection. Following oral administration of FIBRICOR in healthy volunteers, median peak plasma levels of fenofibric acid occur by approximately 2.5 hours after administration. Exposure after administration of 3 × 35 mg FIBRICOR tablets is comparable to 1 × 105 mg FIBRICOR tablets.

A food-effect study involving administration of FIBRICOR to healthy volunteers under fasting conditions and with a high-fat meal indicated that the Cmax was decreased by approximately 35% while the AUC remained unchanged. This decrease in exposure is not considered clinically significant, and therefore FIBRICOR can be taken without regards to meals.

The extent and rate of absorption of fenofibric acid after administration of 105 mg FIBRICOR tablets are equivalent to those after administration of 145 mg fenofibrate tablets (TriCor®) under fasted 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 slightly more than double those following a single dose. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.

Metabolism

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 vitro and in vivo metabolism data indicate that fenofibric acid does not undergo oxidative metabolism (e.g. cytochrome P450) to a significant extent. The enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 do not play a role in the metabolism of fenofibric acid.

Elimination

After absorption, fenofibric acid is eliminated with a half-life of approximately 20 hours, allowing once-daily dosing.

Specific Populations

Geriatrics: In five 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 an equivalent dose of FIBRICOR can be used in elderly subjects with normal renal function, without increasing accumulation of the drug or metabolites [see Use in Specific Populations (8.5) and Dosage and Administration (2.5)].

Pediatrics : The pharmacokinetics of FIBRICOR 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 fenofibric acid has not been studied, however, fenofibric acid 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/1.73m2) 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 (eGFR 30 – 59 mL/min/1.73m2) renal impairment 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 FIBRICOR should be avoided in patients who have severe renal impairment and dose reduction is required in patients with mild-to-moderate renal impairment.

Hepatic Impairment: No pharmacokinetic studies of fenofibric acid 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 fenofibric acid on exposure to other drugs.

Table 2. Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from FIBRICOR or Fenofibrate Administration
*
TriCor® (fenofibrate) oral tablet
TriCor® (fenofibrate) oral micronized capsule
Co-Administered Drug Dosage Regimen of Co-Administered Drug Dosage Regimen of Fenofibrate Changes in Fenofibric Acid Exposure
AUC Cmax
No dosing adjustment required for FIBRICOR with the following co-administered drugs
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 × 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 FIBRICOR or Fenofibrate Co-Administration on Systemic Exposure of Other Drugs
*
TriCor® (fenofibrate) oral tablet
TriCor® (fenofibrate) oral micronized capsule
Dosage Regimen of Fenofibrate Dosage Regimen of Co-Administered Drug Change in Co-Administered Drug Exposure
Analyte AUC Cmax
No dosing adjustment required for these co-administered drugs with FIBRICOR
Lipid-lowering agents
Fenofibrate 160 mg * once daily for 10 days Atorvastatin, 20 mg once daily for 10 days Atorvastatin ↓17% 0%
Fenofibrate 3 × 67 mg as a single dose Pravastatin, 40 mg as a single dose Pravastatin ↑13% ↑13%
3α-hydroxyl-iso-pravastatin ↑26% ↑29%
Fenofibrate 160 mg * once daily for 10 days Pravastatin, 40 mg once daily for 10 days Pravastatin ↑28% ↑36%
3α-hydroxyl-iso-pravastatin ↑39% ↑55%
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%
Anti-viral agents
FIBRICOR 105 mg once daily for 10 days Efavirenz, 600 mg as a single dose Efavirenz ↓8% ↑1%

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