Antara (Page 4 of 7)

12.2 Pharmacodynamics

A variety of clinical studies have demonstrated that elevated levels of total-C, DL-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 All) 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 triglycerides, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering 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 apoproteins Apo AI and Apo AII.

12.3 Pharmacokinetics

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 radiolabeled 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 from Antara capsules 90 mg occur within 2 to 6 hours after administration.

In the presence of a high-fat meal, there was a 26.7% increase in AUC and 15.35% increase in Cmax of fenofibric acid from Antara capsule 30mg relative to fasting state,

Distribution

In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within a week of dosing and did not demonstrate accumulation across time following multiple dose administration. 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 radiolabeled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.

Fenofibrate acid from Antara is eliminated with a half-life of 23 hours, allowing once daily dosing.

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 the elderly with normal renal function, without increasing accumulation of the drug or metabolites [see Dosage and Administration (2.4) and Use in Special Populations (8.5) ].

Pediatrics

The pharmacokinetics of Antara 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 (creatinine clearance [CrCl] ≤ 30 mL/min or estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m2) 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 (CrCl 30-80 mL/min or 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 Antara 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 having hepatic impairement.

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 inhibitor 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 Antara 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 Cm a x
No dosing adjustments required for Antara with the following co administered drugs
Lipid lowing 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 once daily 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 Antara 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 Changes in Co Administered Drug Exposure
Analyte AUC Cm a x
No dosing adjustments required for these co administered drugs with Antara
Lipid lowing 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 Pravastatin ↑13% ↑13%
3α-Hydroxyl-isopravastatin ↑26% ↑29%
Fenofibrate 160 mg * once daily for 10 days Pravastatin, 40 mg once daily for 10 days Pravastatin ↑28% ↑36%
3α-Hydroxyl-isopravastatin ↑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 once daily 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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