Actions of Lipil in details
Antihyperlipidemic.
Pharmacology: Pharmacodynamics: Lipil is a prodrug and has no antilipemic activity until it is hydrolyzed by tissue and plasma esterases in vivo to fenofibric acid.
The lipid modifying effects of Lipil are mediated by the activation of peroxisome proliferator activated receptor type alpha (PPARα). Through this mechanism, Lipil increases lipolysis and elimination of atherogenic triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The reduction in triglyceride concentrations alters the size and composition of low-density lipoprotein cholesterol (LDL-C) from small, dense particles to larger, more buoyant particles that are less atherogenic and more rapidly catabolized. PPARα activation also induces an increase in the synthesis of apo A-I, A-II, and high-density lipoprotein (HDL)-cholesterol.
Fenofibric acid decreases total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), very low-density lipoprotein (VLDL)-cholesterol, and triglycerides (TG). In addition, fenofibric acid increases HDL-C, apoproteins A-I and A-II.
Lipil has been shown to reduce serum uric acid concentrations in healthy and hyperuricemic individuals by increasing the urinary excretion of uric acid.
Pharmacokinetics: Lipil is rapidly absorbed after oral administration. The extent of Lipil absorption is comparable between fed (60-90%) and fasted (30-50%) conditions. Food increases the rate of Lipil absorption by approximately 55%.
After oral administration of a 160 mg capsule (Lipil), to fasted adults, mean peak Lipil plasma concentration (14.3233±2.1269 mcg/mL) is achieved within 4.88±0.9 hrs (Tmax).
The volume of distribution of fenofibric acid is 0.89 L/kg and the active metabolite is 99% protein bound.
After oral administration, Lipil is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid. No unchanged Lipil is detected in plasma of healthy subjects after administration. 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 Lipil nor fenofibric acid undergo oxidative metabolism to a significant extent.
After absorption, Lipil is excreted mainly in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabeled Lipil, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces. Fenofibric acid is eliminated with a t½ of approximately 16 hrs, allowing once daily administration in a clinical setting.
The t½ of fenofibric acid is prolonged in the elderly (39 hrs) and in the presence of hepatic dysfunction (45-57 hrs). In severe renal failure, the t½ is markedly prolonged (143 hrs) and during repeated administration of Lipil, fenofibric acid accumulates in the plasma. Dose adjustment is necessary in such patients.
How should I take Lipil?
Take Lipil exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Take the medicine with a full glass of water.
You may take Lipil with or without food.
If you also take cholestyramine (Questran), colesevelam (Welchol), or colestipol (Colestid), take these medicines at least 1 hour after taking Lipil, or 4 to 6 hours before taking Lipil. Do not take any of these medicines at the same time you take fenofibric acid.
"Statin" cholesterol-lowering medications may be taken at the same time as Lipil.
Lipil is only part of a complete program of treatment that may also include diet, exercise, weight control, and other medications. Follow your diet, medication, and exercise routines very closely.
To best treat your condition, use all of your medications as directed by your doctor. Be sure to read the medication guide or patient instructions provided with each of your medications. Do not change your doses or medication schedule without advice from your doctor.
To be sure Lipil is helping your condition and not causing harmful effects, your blood will need to be tested on a regular basis. Your kidney, liver, and gallbladder function may also need to be tested. Visit your doctor regularly.
Store Lipil at room temperature away from moisture and heat.
Lipil administration
Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.
Some brands of Lipil should be taken with meals to help your body better absorb the medicine. Other brands may be taken with or without food. Follow the directions on your medicine label.
Use Lipil regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.
If you also take cholestyramine, colesevelam, colestipol: these other medicines should be taken at least 1 hour after or 4 hours before you take Lipil.
Lipil is only part of a treatment program that may also include diet, exercise, and weight control. Follow your doctor's instructions very closely.
While using Lipil, you may need frequent blood tests at your doctor's office. Your liver and gallbladder function may also need to be tested.
Store at room temperature away from moisture, heat, and light. Keep the tablets in their original container, along with the packet or canister of moisture-absorbing preservative.
Lipil pharmacology
Mechanism of Action
The active moiety of Lipil is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of Lipil.
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, Lipil 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 (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 apolipoproteins A-I, A-II and HDL-cholesterol.
Lipil also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.
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 Lipil, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides and triglyceride rich lipoprotein (VLDL) in treated patients. In addition, treatment with Lipil results in increases in high density lipoprotein (HDL) and apolipoproteins apoAI and apoAII.
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 Lipil capsule.
Lipil is a pro-drug of the active chemical moiety fenofibric acid. Lipil 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 Lipil cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, Lipil is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled Lipil 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 Lipil is administered under fasting or nonfasting conditions.
Distribution
Upon multiple dosing of Lipil, 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, Lipil is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged Lipil 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 Lipil nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.
Elimination
After absorption, Lipil is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled Lipil, 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 Lipil 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.
Pediatrics
The pharmacokinetics of Lipil has not been studied in pediatric populations.
Gender
No pharmacokinetic difference between males and females has been observed for Lipil.
Race
The influence of race on the pharmacokinetics of Lipil has not been studied, however Lipil 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 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 30-59 mL/min/1.73m2) 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 Lipil should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment.
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 Lipil 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 Lipil or fenofibric acid on other drugs.
| Co-Administered Drug | Dosage Regimen of Co-Administered Drug | Dosage Regimen of Lipil | Changes in Fenofibric Acid Exposure | ||
| AUC | Cmax | ||||
| Lipid-lowering agents | |||||
| Atorvastatin | 20 mg once daily for 10 days | Lipil 160 mg1 once daily for 10 days | ↓2% | ↓4% | |
| Pravastatin | 40 mg as a single dose | Lipil 3 x 67 mg2 as a single dose | ↓1% | ↓2% | |
| Fluvastatin | 40 mg as a single dose | Lipil 160 mg1 as a single dose | ↓2% | ↓10% | |
| Anti-diabetic agents | |||||
| Glimepiride | 1 mg as a single dose | Lipil 145 mg1 once daily for 10 days | ↑1% | ↓1% | |
| Metformin | 850 mg three times daily for 10 days | Lipil 54 mg1 three times daily for 10 days | ↓9% | ↓6% | |
| Rosiglitazone | 8 mg once daily for 5 days | Lipil 145 mg1 once daily for 14 days | ↑10% | ↑3% | |
| 1 Lipil (Lipil) oral tablet | |||||
| 2 Lipil (Lipil) oral micronized capsule | |||||
| Dosage Regimen of Lipil | Dosage Regimen of Co-Administered Drug | Change in Co-Administered Drug Exposure | ||
| Analyte | AUC | Cmax | ||
| Lipid-lowering agents | ||||
| Lipil 160 mg1 once daily for 10 days | Atorvastatin, 20 mg once daily for 10 days | Atorvastatin | ↓17% | 0% |
| Lipil 3 x 67 mg2 as a single dose | Pravastatin, 40 mg as a single dose | Pravastatin | ↑13% | ↑13% |
| 3α-Hydroxyl-iso-pravastatin | ↑26% | ↑29% | ||
| Lipil 160 mg1 as a single dose | Fluvastatin, 40 mg as a single dose | (+)-3R, 5S-Fluvastatin | ↑15% | ↑16% |
| Anti-diabetic agents | ||||
| Lipil 145 mg1 once daily for 10 days | Glimepiride, 1 mg as a single dose | Glimepiride | ↑35% | ↑18% |
| Lipil 54 mg1 three times daily for 10 days | Metformin, 850 mg three times daily for 10 days | Metformin | ↑3% | ↑6% |
| Lipil 145 mg1 once daily for 14 days | Rosiglitazone, 8 mg once daily for 5 days | Rosiglitazone | ↑6% | ↓1% |
| 1 Lipil (Lipil) oral tablet | ||||
| 2 Lipil (Lipil) oral micronized capsule | ||||
References
- DailyMed. "FENOFIBRATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Fenofibrate: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Fenofibrate: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
The results of a survey conducted on ndrugs.com for Lipil are given in detail below. The results of the survey conducted are based on the impressions and views of the website users and consumers taking Lipil. We implore you to kindly base your medical condition or therapeutic choices on the result or test conducted by a physician or licensed medical practitioners.User reports
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Information checked by Dr. Sachin Kumar, MD Pharmacology
