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At least 19 recordsLinked to original sources
PubMed2003

An open-label, randomized, three-way crossover trial of the effects of coadministration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers.

BACKGROUND: Rosuvastatin and fenofibrate are lipid-regulating agents with different modes of action. Patients with dyslipidemia who have not achieved treatment targets with monotherapy may benefit from the combination of these agents. OBJECTIVE: The effect of coadministration of rosuvastatin and fenofibrate on the steady-state pharmacokinetics of rosuvastatin and fenofibric acid (the active metabolite of fenofibrate) was assessed in healthy volunteers. METHODS: This was an open-label, randomized, 3-way crossover trial consisting of three 7-day treatment periods. Healthy male volunteers received one of the following treatment regimens in each period: rosuvastatin 10 mg orally once daily; fenofibrate 67 mg orally TID; and rosuvastatin + fenofibrate dosed as above. The steady-state pharmacokinetics of rosuvastatin and fenofibric acid, both as substrate and as interacting drug, were investigated on day 7 of dosing. Treatment effects were assessed by construction of 90% CIs around the ratios of the geometric least-square means for rosuvastatin + fenofibrate/rosuvastatin and rosuvastatin + fenofibrate/fenofibrate for the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (derived from analysis of variance of log-transformed parameters). RESULTS: Fourteen healthy male volunteers participated in the study. When rosuvastatin was coadministered with fenofibrate, there were minor increases in the AUC from 0 to 24 hours and maximum concentration (Cmax) of rosuvastatin: the respective geometric least-square means increased by 7% (90% CI, 1.00-1.15) and 21% (90% CI, 1.14-1.28). The pharmacokinetic parameters of fenofibric acid were similar when fenofibrate was dosed alone and with rosuvastatin: the geometric least-square means for fenofibric acid AUC from 0 to 8 hours and Cmax decreased by 4% (90% CI, 0.90-1.02) and 9% (90% CI, 0.84-1.00), respectively. The treatments were well tolerated alone and in combination. CONCLUSION: Coadministration of rosuvastatin and fenofibrate produced minimal changes in rosuvastatin and fenofibric acid exposure.

Adult↗
PubMed2000

Effect of combined fluvastatin-fenofibrate therapy compared with fenofibrate monotherapy in severe primary hypercholesterolemia. French Fluvastatin Study Group.

This double-blind study was designed to assess the efficacy and safety of fluvastatin-fenofibrate combination therapy compared with fenofibrate monotherapy in severe primary hypercholesterolemia (low-density lipoprotein [LDL] cholesterol > or =190 mg/dl [4.9 mmol/L], triglycerides < or =350mg/dl [3.9 mmol/l]). After a 10-week placebo and dietary baseline period, 102 patients were randomized to receive micronized fenofibrate 200 mg, fluvastatin 20 mg plus micronized fenofibrate 200 mg, or fluvastatin 40 mg plus micronized fenofibrate 200 mg. At week 16, fenofibrate 200 mg alone lowered LDL cholesterol from baseline by 21% compared with 32% for fluvastatin 20 mg plus fenofibrate 200 mg and 41% for fluvastatin 40 mg plus fenofibrate 200 mg (p <0.001). Triglycerides decreased by 29% with fenofibrate 200 mg alone, 39% with fluvastatin 20 mg plus fenofibrate 200 mg, and 40% with fluvastatin 40 mg plus fenofibrate 200 mg (p <0.05). Safety was assessed by recording adverse events and measuring clinical laboratory parameters. The adverse event profile was similar for the 3 treatment groups. One patient withdrew due to an increase in transaminase levels. No significant increase in creatine phosphokinase levels was observed with combination therapy. In conclusion, the addition of fluvastatin to micronized fenofibrate results in substantial improvement in atherogenic plasma lipids and is well tolerated.

Aged↗
PubMed1997

Relationship between plasma fenofibric acid levels and the effect of micronized fenofibrate on cholesterol, low-density-lipoprotein cholesterol and apolipoprotein B in patients with primary hypercholesterolemia.

OBJECTIVE: We examined the relationship between plasma levels of fenofibric acid, the active metabolite of fenofibrate, and differences in concentrations of plasma lipids, in subjects with primary type IIA or IIB hyperlipoproteinemia (HLP). SUBJECTS AND METHODS: Twenty-nine patients (13 with type IIA and 16 with type IIB HLP) were treated with a single daily 200-mg dose of micronized fenofibrate for 3 months, after which the plasma levels of fenofibric acid were determined by HPLC after an overnight fast. RESULTS: In the type IIA HLP phenotype, statistically significant correlations were found between fenofibric acid levels and changes in total cholesterol, LDL-C and apo-B at all three control visits, with the highest correlation coefficients at V3 visit (total cholesterol r = 0.85. LDL-C r = 0.68, apo-B r = 0.85). In type IIB HLP, statistical significance was confirmed only when performing an analysis of pooled values for total cholesterol and LDL-C (r = 0.42, r = 0.34, respectively). The high correlation between plasma fenofibric acid levels and its effect on beta lipoprotein changes might reflect the effect of fenofibrate on the catabolism of plasma LDL by the LDL receptor, since that type of relationship is typical of drugs which directly influence the target compartment without an effect on intermediary steps of metabolism. An explanation for the different levels of correlations in type IIA and IIB patients might be found in their different metabolic defects. The fact that fenofibrate's impact on VLDLs is such an important part of its effect on lipoprotein metabolism supports the concept that the effect of circulating fenofibric acid is less pronounced on the LDL receptor in type IIB HLP.

Adult↗
PubMed2001

Both fenofibrate and atorvastatin improve vascular reactivity in combined hyperlipidaemia (fenofibrate versus atorvastatin trial--FAT).

OBJECTIVE: It has been repeatedly proven that statins improve endothelial function in isolated hypercholesterolaemia but there is far less evidence in the case of combined hyperlipidaemia. Studies assessing the effects of fibrates on endothelium have been neglected. Therefore, we conducted a trial in which the effects of fenofibrate and atorvastatin monotherapy on both endothelium-dependent vascular reactivity and biochemical parameters were compared in patients with combined hyperlipidaemia. METHODS: 29 otherwise healthy males (aged 47.4+/-7.8 years) with combined hyperlipidaemia (total cholesterol 7.55+/-1.20 mmol/l, triglycerides 5.41+/-4.54 mmol/l) were included into the randomised, single-blind, cross-over study to receive either 200 mg of micronised fenofibrate or 10 mg of atorvastatin daily--each of the drugs for a period of 10 weeks. Analysed biochemical parameters were as follows: serum total-, LDL- and HDL-cholesterol, apolipoproteins A-I and B, triglycerides, fibrinogen, uric acid, C-reactive protein (CRP), insulin, and homocysteine. Endothelial function was investigated by duplex Doppler ultrasonography at the brachial artery. Two indices of endothelial-dependent postischaemic changes were used - the recently introduced index of peak blood flow (PBF) representing the level of reactive hyperaemia and traditional flow-mediated dilatation (FMD). RESULTS: We observed a small improvement in FMD after both fenofibrate and atorvastatin (from 2.26% to 2.98% and 2.87%, respectively; NS). PBF increased from 448 ml/min to 536 ml/min after fenofibrate (P=0.04) and to 570 ml/min after atorvastatin (P=0.03). The effects of both fenofibrate and atorvastatin on endothelial function did not differ significantly (P-values of 0.82 and 0.47 for FMD and PBF, respectively). Significant correlations (P<0.01) between the changes of vascular reactivity and biochemical indices were found between FMD and CRP (r=-0.60) and between both FMD and PBF, and insulinaemia (r=-0.48 and -0.56, respectively) only during treatment with fenofibrate. CONCLUSIONS: Both fenofibrate and atorvastatin significantly improved endothelium-dependent vascular reactivity without mutual difference. The PBF was superior to FMD for the detection of this improvement. The beneficial effect of both drugs did not correlate with the change of lipid profile during therapy. The improvement of vascular reactivity during treatment with fenofibrate (opposed to atorvastatin) was related to the reduction of indirect marker of chronic vessel wall inflammation and of insulin resistance. The PBF was more reproducible than FMD because of considerably lower intra-subject variability.

Adult↗
PubMed2004

Fenofibrate and fenofibric acid analysis by capillary electrophoresis.

A capillary electrophoresis method has been developed to measure fenofibrate in capsules based on micellar electrokinetic capillary chromatography with detection at 280 nm using a borate buffer containing sodium dodecyl sulfate (SDS). However, the metabolite of this drug (fenofibric acid) in serum and whole blood was analyzed by capillary zone electrophoresis (CZE) in a borate-carbonate buffer using acetonitrile stacking. The analysis is rapid, < 7 min with no interferences. Incubation of fenofibrate in whole blood caused hydrolysis of the ester bond with the release of fenofibric acid.

Electrophoresis, Capillary↗
PubMed1990

Safety, tolerability, and efficacy of simvastatin and fenofibrate--a multicenter study. Simvastatin-Fenofibrate Study Group.

Five centers participated in a double-blind, randomized, active-drug controlled study. The selected patients had a diagnosis of primary hypercholesterolemia (phenotype IIa or IIb, total cholesterol [TC] greater than 300 mg/dl, low-density lipoprotein [LDL] cholesterol greater than 195 mg/dl, triglycerides [TG] less than 350 mg/dl). Throughout the study the patients observed a lipid-lowering diet (American Heart Association). After a baseline placebo period (4 weeks), the patients were randomly assigned to simvastatin 20 mg q.p.m. or fenofibrate 200 mg b.i.d. If after 6 weeks of treatment the LDL cholesterol level remained over 140 mg/dl the dose of simvastatin was doubled. The total duration of treatment was 10 weeks. One hundred eighty-four patients completed the study; age ranged from 17 to 72 years (mean 46; 129 men, 55 women). Seventy-nine patients had ischemic heart diseases. Simvastatin significantly reduces TC, LDL, and apolipoprotein (apo) B (30%, 35%, and 27%, respectively). These effects are larger than those of fenofibrate (19%, 22%, and 14%, respectively). Fenofibrate decreased very-low-density lipoprotein and TG, and increased high-density lipoprotein and apo A1, to a larger extent than simvastatin. However, the difference reached statistical significance only for TG (29% versus 17%). Both drugs were well tolerated. Clinical adverse experiences occurred with a low frequency, and few of these were considered drug related (6 and 8% in the simvastatin and fenofibrate groups, respectively). Only two patients had serious laboratory adverse experiences considered drug related or possibly drug related (one in each treatment group with increased SGPT, gamma-GT, and/or creatine phosphokinase).

Adolescent↗
PubMed2005

Fenofibric acid, an active form of fenofibrate, increases apolipoprotein A-I-mediated high-density lipoprotein biogenesis by enhancing transcription of ATP-binding cassette transporter A1 gene in a liver X receptor-dependent manner.

OBJECTIVE: Fibrates are widely used drugs to reduce plasma triglyceride and increase high-density lipoprotein. Their active forms, fibric acids, are peroxisome proliferator-activated receptor-alpha activators, but no direct evidence has been demonstrated for their activation of ATP-binding cassette transporter A1 (ABCA1) in relation to clinically used fibrates. We investigated the reaction of fenofibric acid in this regard. METHODS AND RESULTS: Fenofibric acid was examined for the effect of increase of ABCA1 activity. It enhanced ABCA1 gene transcription and its protein level in macrophage cell line cells and fibroblasts and increased apolipoprotein A-I-mediated cellular lipid release, all in a dose-dependent manner. Enhancement of the gene transcription was examined by using a reporter assay system for liver X receptor responsive element (LXRE) and its inactive mutant. The results demonstrated that the effect of fenofibric acid is dependent on active LXRE. CONCLUSIONS: Fenofibric acid increased transcription of ABCA1 gene in a liver X receptor-dependent manner.

ATP Binding Cassette Transporter 1↗
PubMed1998

[High-performance liquid chromatographic method for the determination of fenofibric acid and reduced fenofibric acid in human blood, plasma and urine].

In this study, a very reliable HPLC method was developed for the determination of fenofibric acid and reduced fenofibric acid in the biological samples described as follows. After addition of the internal standard solution and 0.5 M HCl to the biological sample, fenofibric acid, reduced fenofibric acid and the internal standard were extracted with a mixed solvent of n-hexane and ethyl acetate (90:10) from the mixture. The acids were back-extracted from the organic phase with 0.1 M Na2HPO4 and then re-extracted from the aqueous phase with a mixed solution of n-hexane and ethyl acetate (95:5) after addition of 0.5 M HCl. The organic phase was evaporated to dryness under the vacuum. The residue was dissolved in MeOH and diluted with distilled water. An aliquot of the resulting solution was injected on the HPLC. High reproducibility was observed in this HPLC method (C.V.% less than 4%). Moreover it was confirmed that the conjugates in the urine could be hydrolyzed by incubation at 37 degrees C for 18 h after addition of 400 IU of beta-glucuronidase.

Administration, Oral↗
PubMed1980

[Metabolism of fenofibrate and fenofibric acid in vivo and in cultures of liver epithelial cells (author's transl)].

In vitro and in vivo studies using capillary column gas chromatography alone or coupled with mass spectrometry resulted in the identification of several metabolites of fenofibrate (LF 178). Fenofibric acid (LF 153) was omnipresent, being found in rats after acute, subacute and chronic administration, in human urine during chronic treatment, and in cultures of rat and human liver cells. Other metabolites were LF 433 (LF 153 benzhydrol), which increases in rats with the duration of treatment while LF 153 decreases, and LF - phenol" found in human urine. In hepatocyte cultures, fenofibric acid was predominant, but fenofibrate itself and LF 321 (LF 178 benzhydrol) were also present in addition to the above-mentioned metabolites. LF 321, however, was only found in human liver cell cultures.

Animals↗
PubMed2005

Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study: baseline characteristics and short-term effects of fenofibrate [ISRCTN64783481].

OBJECTIVE: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study is examining the effects of long-term fibrate therapy on coronary heart disease (CHD) event rates in patients with diabetes mellitus. This article describes the trial's run-in phase and patients' baseline characteristics. RESEARCH DESIGN AND METHODS: FIELD is a double-blind, placebo-controlled trial in 63 centres in 3 countries evaluating the effects of fenofibrate versus placebo on CHD morbidity and mortality in 9795 patients with type 2 diabetes mellitus. Patients were to have no indication for lipid-lowering therapy on randomization, but could start these or other drugs at any time after randomization. Follow-up in the study was to be for a median duration of not less than 5 years and until 500 major coronary events (fatal coronary heart disease plus nonfatal myocardial infarction) had occurred. RESULTS: About 2100 patients (22%) had some manifestation of cardiovascular disease (CVD) at baseline and thus high risk status. Less than 25% of patients without CVD had a (UKPDS determined) calculated 5-year CHD risk of <5%, but nearly all had a 5-year stroke risk of <10%. Despite this, half of the cohort were obese (BMI > 30), most were men, two-thirds were aged over 60 years, and substantial proportions had NCEP ATP III features of the metabolic syndrome independent of their diabetes, including low HDL (60%), high blood pressure measurement (41%), high waist measurement (65%), and raised triglycerides (52%). After a 6-week run-in period before randomisation with all participants receiving 200 mg comicronized fenofibrate, there were declines in total and LDL cholesterol (10%) and triglycerides (26%) and an increase in HDL cholesterol (6.5%). CONCLUSION: The study will show the effect of PPAR-alpha agonist action on CHD and other vascular outcomes in patients with type 2 diabetes including substantial numbers with low to moderate CVD risk but with the various components of the metabolic syndrome. The main results of the study will be reported in late 2005.

Aged↗
PubMed2006

The transfer of a LC-UV method for the determination of fenofibrate and fenofibric acid in Lidoses: use of total error as decision criterion.

Two new statistical approaches to assess the validity of the transfer of a LC-UV method for the determination of fenofibrate and fenofibric acid were investigated and compared to the conventional approaches generally used in this domain. These new approaches, namely the Tolerance Interval and the Risk approaches, are based on the simultaneous evaluation of the systematic (or trueness) and random (or precision) errors of the transfer into a single criterion called total error (or accuracy). The results of the transfer showed that only the total error based approaches fulfilled the objective of an analytical method transfer, i.e. to give guarantees that each future measurement made by the receiving laboratory will be close enough to the true value of the analyte in the sample. Furthermore the Risk approach was the most powerful one and allowed the estimation of the risk to have future measurements out of specification in the receiving laboratory, therefore being a risk management tool.

Chromatography, Liquid↗
PubMed1999

Micronized fenofibrate: a new fibric acid hypolipidemic agent.

OBJECTIVE: To review the efficacy and safety of fenofibrate in the management of hyperlipidemias. DATA SOURCES: A MEDLINE search (1974-October 1998), Current Contents search, additional references from article bibliographies, and the package insert from the manufacturer were used to identify data for evaluation. Studies evaluating fenofibrate (peer-reviewed publications, package insert data) were considered for inclusion. Abstracts and data on file with the manufacturer were not considered for inclusion. STUDY SELECTION: English-language literature was reviewed to evaluate the pharmacology, pharmacokinetics, clinical use, and tolerability of fenofibrate. Data from animals and in vitro systems were included only when necessary to explain the drug's pharmacology. DATA SYNTHESIS: Micronized fenofibrate is a fibric acid derivative approved by the Food and Drug Administration (FDA) in February 1998 for the treatment of types IV and V hyperlipidemia. Data from the peer-reviewed literature also support the use of fenofibrate in types IIa, IIb, and III hyperlipidemias. Micronized fenofibrate 67-201 mg/d is useful as monotherapy or as an adjunct to other hypolipidemics and dietary therapy. In placebo-controlled clinical trials, regular formulation fenofibrate 300-400 mg/d lowered serum triglyceride (TG) concentrations by 24-55%, total cholesterol by 9-25%, low-density lipoprotein cholesterol (LDL-C) concentrations by 6-35%, and raised high-density lipoprotein cholesterol (HDL-C) concentrations by 8-38%. Few comparative data exist regarding fenofibrate versus clofibrate and gemfibrozil. In noncomparative and comparative clinical trials, fenofibrate appeared to be well tolerated. The most common causally related adverse events were digestive, musculoskeletal, and dermatologic in nature. Concurrent use of fenofibrate and a hydroxymethylglutaryl-coenzyme A inhibitor may increase the risk of myopathy and/or rhabdomyolysis, although recent data suggest that concurrent use of fenofibrate with low-dose simvastatin or pravastatin is safe. Fenofibrate may enhance the effect of oral anticoagulants. CONCLUSIONS: Fenofibrate reduces serum TG, total cholesterol, and LDL-C, and raises HDL-C to clinically relevant degrees. Its spectrum of activity appears to exceed that recommended for types IV and V hyperlipidemia to encompass types IIa, IIb, and III hyperlipidemias as well. To this extent, it may be considered a broader-spectrum fibrate than is indicated by its FDA approval. Adverse effects of fenofibrate appear to be similar to those of other fibrates and require routine monitoring (clinical, liver function). Long-term safety data are readily available from drug registries in many countries where the product has been available for nearly two decades. Cost-effectiveness studies comparing fenofibrate with other hypolipidemics demonstrate benefits of fenofibrate over simvastatin in types IIa and IIb hyperlipidemia. The need for dosage titration of the micronized preparation from 67 mg/d upward to a final dose of 200 mg/d is also not supported by peer-reviewed literature (except in the case of renal impairment). Although preliminary data on plaque regression are encouraging, published clinical studies evaluating the impact of fenofibrate on cardiovascular morbidity and mortality are awaited. Micronized fenofibrate is worthy of formulary inclusion.

Clinical Trials as Topic↗
PubMed2004

Effect of colesevelam HCl on single-dose fenofibrate pharmacokinetics.

OBJECTIVE: The primary aim of this study was to determine whether there is an effect of colesevelam HCl (WelChol; Sankyo Pharma Inc., Parsippany, NJ, USA) on fenofibric acid (active metabolite of fenofibrate, TriCor, Abbott Laboratories, North Chicago, IL, USA) pharmacokinetics following single-dose fenofibrate when colesevelam HCl and fenofibrate are administered concomitantly, or when colesevelam HCl is administered 4 hours following fenofibrate therapy. METHODS: Thirty healthy volunteers were enrolled in a randomised, open-label, three-way crossover, drug interaction study. Subjects received one of three treatments at each of three dose administration periods: (i) treatment A -- fenofibrate 160 mg plus colesevelam HCl 3750 mg (6 x 625 mg tablets) administered with breakfast; (ii) treatment B -- fenofibrate 160 mg administered with breakfast, followed 4 hours later by colesevelam HCl 3750 mg (6 x 625 mg tablets) administered with lunch; or (iii) treatment C -- fenofibrate 160 mg administered with breakfast. Treatments were separated by a 10-day washout period. Blood samples were collected at predetermined time intervals, both before and after drug administration. Plasma concentrations of fenofibrate and fenofibric acid were measured using a validated liquid chromatography/mass spectroscopy/mass spectroscopy method. RESULTS: Area under the concentration-time curve (AUC) from time zero to the timepoint of the lowest quantifiable concentration (AUCt), AUC from time zero to infinity (AUCinfinity) and maximum plasma concentration (Cmax) for fenofibric acid were 92.1%, 93.9% and 79.8%, respectively, of control values when colesevelam HCl and fenofibrate were coadministered with breakfast; and 91.9%, 93.9% and 99.1%, respectively, when fenofibrate was administered followed 4 hours later by administration of colesevelam HCl. The 90% confidence intervals for the ratios of geometric means for AUCt, AUCinfinity and Cmax comparing the three treatments were contained within the 80-125% equivalence range, with the exception of Cmax for treatment A. Coadministration of fenofibrate with colesevelam HCl resulted in an approximate 20% reduction in Cmax of the active metabolite (fenofibric acid). There were no significant differences in the time to Cmax, elimination rate constant or elimination half-life between any of the treatment groups. CONCLUSIONS: Colesevelam HCl had no significant effect on fenofibrate bioavailability when administered either concomitantly with fenofibrate or 4 hours after fenofibrate.

Adult↗
PubMed2006

An open-label, crossover study of the pharmacokinetics of Insoluble Drug Delivery-MicroParticle fenofibrate in combination with atorvastatin, simvastatin, and extended-release niacin in healthy volunteers.

BACKGROUND: Fenofibrate has been prescribed concomitantly with other lipid-lowering agents as a treatment for dyslipidemia. However, combination therapy, particularly a statin-fibrate combination, may be associated with an increased risk of myopathy, although this risk appears to be less with fenofibrate than with other fibrates. OBJECTIVE: The objective of this study was to determine the effect of administering a single dose of atorvastatin, simvastatin, or extended-release (ER) niacin on the pharmacokinetics and safety of a single dose of fenofibrate Insoluble Drug Delivery-MicroParticle (IDD-P). METHODS: This was an open-label, single-center,randomized, 4-treatment, 4-period crossover study in healthy adult volunteers. Subjects were randomized to 1 of 4 treatment sequences, administered 1 week apart, that included all 4 of the following treatments: 1 IDD-P fenofibrate 160-mg tablet alone; 1 IDD-P fenofibrate 160-mg tablet plus 1 atorvastatin 10-mg tablet; 1 IDD-P fenofibrate 160-mg tablet plus 1 simvastatin 10-mg tablet; and 1 IDD-P fenofibrate 160-mg tablet plus 1 ER niacin 500-mg tablet. Blood samples for pharmacokinetic analysis were obtained immediately before and up to 72 hours after administration during each of the 4 treatment periods. If the 90% CI for the log-transformed parameter was between 0.80 and 1.25, and the 90% CI for the nontransformed parameter was between 0.80 and 1.20, then the absence of a clinically significant drug interaction was assumed. However, the absence of a drug interaction was not to be ruled out if one or more of the CIs exceeded the boundary, provided the CI included 1.00. RESULTS: Twenty healthy subjects were enrolled. Sixteen (80%) of the subjects were male and 17 (85%) were black; mean (SD) age was 35 (9.3) years. The mean C(max), AUC from the time of administration to the last quantifiable concentration (AUC(0-t)), and AUC from the time of administration to infinity (AUC(0-infinity)) were 5%, 6%, and 2% lower, respectively, with IDD-P fenofibrate plus atorvastatin than with IDD-P fenofibrate alone; the mean C(max), AUC(0-t), and AUC(0-infinity) were 6% lower, and 10% and 9% higher, respectively, with IDD-P fenofibrate plus simvastatin than with IDD-P fenofibrate alone; and the mean C(max), AUC(0-t), and AUC(0-infinity) were 12%, 6%, and 5% lower, respectively, with IDD-P fenofibrate plus ER niacin than with IDD-P fenofibrate alone. The 90% CIs surrounding the mean ratios for AUC(0-infinity) and AUC(0-infinity) for all 3 comparisons were between 0.80 and 1.25, suggesting the absence of a drug interaction for these parameters. For C(max), an absence of a drug interaction was observed between concomitantly administered IDD-P fenofibrate and both atorvastatin and simvastatin; absence of drug interaction was not found for IDD-P fenofibrate plus ER niacin. All treatments were well tolerated; headache was the most common adverse event (AE) (10%). One subject with creatinine kinase levels of 1300 IU/L (>6 times the upper limit of normal) at baseline experienced a seizure approximately 12 to approximately 13 hours after administration of IDD-P fenofibrate plus atorvastatin; this serious AE was deemed to be possibly related to study drug. CONCLUSIONS: Concomitant administration of a single dose of either atorvastatin or simvastatin had no significant effect on the pharmacokinetics of a single dose of IDD-P fenofibrate. A drug interaction between concomitantly administered single doses of IDD-P fenofibrate and ER niacin could not be ruled out.

Administration, Oral↗
PubMed2002

Fenofibrate in the treatment of dyslipidemia: a review of the data as they relate to the new suprabioavailable tablet formulation.

BACKGROUND: The fibric acid derivative fenofibrate is indicated as an adjunct to dietary modification in adults with primary hypercholesterolemia or mixed dyslipidemia (types IIa and IIb hyperlipidemia, Fredrickson classification) to reduce levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), and apolipoprotein (apo) B, and to increase levels of high-density lipoprotein cholesterol (HDL-C) and apo A. It is also indicated as adjunctive therapy to diet for the treatment of hypertriglyceridemia (types IV and V hyperlipidemia). Initially approved in the United States in a micronized capsule formulation, fenofibrate is now available in a new "suprabioavailable" tablet formulation that has increased bioavailability, achieving equivalent plasma concentrations at lower doses. The 67- and 200-mg micronized capsules can be considered equivalent to the 54- and 160-mg suprabioavailable tablets, respectively. OBJECTIVE: This paper reviews the pharmacologic properties, clinical usefulness, and safety profile of fenofibrate in the management of dyslipidemias. METHODS: Recent studies, abstracts, reviews, and consensus statements published in the English-language literature were identified through searches of MEDLINE (1966-January 2002), International Pharmaceutical Abstracts (1970-January 2002), and PharmaProjects (1990-January 2002) using the search terms fenofibrate, fibrates, hyperlipidemia, hypertriglyceridemia, and dyslipidemia. RESULTS: Fenofibrate is well absorbed after oral administration, with peak plasma levels attained in 6 to 8 hours. The absolute bioavailability of fenofibrate cannot be determined due to its being virtually insoluble in aqueous media suitable for injection; however, after oral administration of a single dose of radiolabeled fenofibrate, approximately 60% of the dose appeared in urine, primarily as fenofibric acid and its glucuronated conjugate, and approximately 25% was excreted in the feces. The apparent volume of distribution is 0.89 L/kg in healthy volunteers, and protein binding is approximately 99% in healthy and hyperlipidemic patients. Neither fenofibrate nor fenofibric acid appears to undergo significant oxidative metabolism in vivo. Fenofibric acid has a half-life of 20 hours. Fenofibrate is effective in lowering TG levels and increasing HDL-C levels. Its LDL-C-lowering effect is greater than that of gemfibrozil. Adverse effects of fenofibrate appear to be similar to those of other fibrates, including gastrointestinal symptoms, cholelithiasis, hepatitis, myositis, and rash. Fenofibrate therapy has been associated with increases in serum aminotransferase levels, and clinical monitoring of these markers of liver function should be performed regularly. CONCLUSIONS: Fenofibrate is effective in reducing levels of TG, TC, and LDL-C, and increasing levels of HDL-C in patients with dyslipidemias. Its efficacy and tolerability in the treatment of hypertriglyceridemia and combined hyperlipidemia have been demonstrated in numerous clinical trials. Its use is accompanied by a low incidence of adverse effects and laboratory abnormalities. Fenofibrate protects against coronary heart disease not only through its effects on lipid parameters but also by producing alterations in LDL structure and, possibly, alterations in the various hemostatic parameters. Its uricosuric property may prove to be a useful adjunctive attribute.

Adult↗
PubMed1989

The biochemical pharmacology of fenofibrate.

Fenofibrate is metabolized in several stages. First, the carboxyl ester moiety is cleaved by hydrolysis, resulting in fenofibric acid, the main pharmacologically active compound. Fenofibric acid, in turn, undergoes carbonyl reduction, resulting in a pharmacologically active metabolite referred to as reduced fenofibric acid. Both fenofibric acid and reduced fenofibric acid may be conjugated to form glucuronides. There are important species differences in the metabolism and elimination patterns of fenofibrate. In the rat and dog, fenofibric acid and reduced fenofibric acid are the principal metabolites. In humans, the glucuronide of fenofibric acid is predominant. In the rat and dog, approximately 70-80% of fenofibrate and its metabolites are recovered in the feces, whereas in humans approximately 65% of the dose is excreted in the urine. Several mechanisms contribute to fenofibrate's hypolipidemic action, including inhibition of fatty acid synthesis, stimulation of fatty acid beta-oxidation, inhibition of triglyceride synthesis, and enhancement of lipoprotein lipase activity. Fenofibrate's hypocholesterolemic action is a result of both decreased biosynthesis of cholesterol through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and increased low-density lipoprotein (LDL) clearance via modulation of hepatic LDL receptors. Fenofibrate also has three other actions that may result in the prevention or at least slowing of atherogenesis, namely inhibition of cholesterol esterification, platelet aggregation, and platelet-derived growth factor. The native acyl glucuronide of fenofibric acid is very stable, and is unlikely to have any toxic potential. Although the elimination half-life of fenofibrate is prolonged in the elderly and in patients with impaired hepatic function, the area under the curve and its clearance are not altered because of compensatory changes in the volume of distribution.

Cholesterol↗
PubMed2002

Micronised fenofibrate: an updated review of its clinical efficacy in the management of dyslipidaemia.

Micronised fenofibrate is a synthetic phenoxy-isobutyric acid derivative (fibric acid derivative) indicated for the treatment of dyslipidaemia. Recently, a new tablet formulation of micronised fenofibrate has become available with greater bioavailability than the older capsule formulation. The micronised fenofibrate 160mg tablet is bioequivalent to the 200mg capsule. The lipid-modifying profile of micronised fenofibrate 160mg (tablet) or 200mg (capsule) once daily is characterised by a decrease in low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels, a marked reduction in plasma triglyceride (TG) levels and an increase in high-density lipoprotein cholesterol (HDL-C) levels. Micronised fenofibrate 200mg (capsule) once daily produced greater improvements in TG and, generally, in HDL-C levels than the hydroxymethylglutaryl coenzyme A reductase inhibitors simvastatin 10 or 20 mg/day, pravastatin 20 mg/day or atorvastatin 10 or 40 mg/day. Combination therapy with micronised fenofibrate 200mg (capsule) once daily plus fluvastatin 20 or 40 mg/day or atorvastatin 40 mg/day was associated with greater reductions from baseline than micronised fenofibrate alone in TC and LDL-C levels. Similar or greater changes in HDL-C and TG levels were seen in combination therapy, compared with monotherapy, recipients. Micronised fenofibrate 200mg (capsule) once daily was associated with significantly greater improvements from baseline in TC, LDL-C, HDL-C and TG levels than placebo in patients with type 2 diabetes mellitus enrolled in the double-blind, randomised Diabetes Atherosclerosis Intervention Study (DAIS) [> or =3 years follow-up]. Moreover, angiography showed micronised fenofibrate was associated with significantly less progression of coronary atherosclerosis than placebo. Micronised fenofibrate has also shown efficacy in patients with metabolic syndrome, patients with HIV infection and protease inhibitor-induced hypertriglyceridaemia and patients with dyslipidaemia secondary to heart transplantation. Micronised fenofibrate was generally well tolerated in clinical trials. The results of a large (n = 9884) 12-week study indicated that gastrointestinal disorders are the most frequent adverse events associated with micronised fenofibrate therapy. Elevations in serum transaminase and creatine phosphokinase levels have been reported rarely with micronised fenofibrate. In conclusion, micronised fenofibrate improves lipid levels in patients with primary dyslipidaemia; the drug has particular efficacy with regards to reducing TG levels and raising HDL-C levels. Micronised fenofibrate is also effective in diabetic dyslipidaemia; as well as improving lipid levels, the drug reduced progression of coronary atherosclerosis in patients with type 2 diabetes mellitus. The results of large ongoing studies (e.g. FIELD with approximately 10 000 patients) will clarify whether the beneficial lipid-modifying effects of micronised fenofibrate result in a reduction in cardiovascular morbidity and mortality.

Cardiovascular Diseases↗