Bezafibrate (DB01393): A Comprehensive Pharmacological and Clinical Review

Section 1: Introduction

Bezafibrate is a well-established second-generation fibric acid derivative, classified as a lipid-modifying agent within the fibrate class of drugs.[1] Patented in 1971 and first approved for medical use in 1978, it has accumulated more than a quarter of a century of therapeutic experience in the management of dyslipidemia.[1] Its primary clinical application is as an adjunct to diet and other non-pharmacological measures for the treatment of various forms of hyperlipidemia, where it effectively reduces elevated levels of triglycerides and cholesterol while increasing high-density lipoprotein cholesterol (HDL-C).[3]

The most defining characteristic of Bezafibrate, which distinguishes it from other fibrates such as fenofibrate and gemfibrozil, is its unique and broad pharmacological profile as a pan-Peroxisome Proliferator-Activated Receptor (pan-PPAR) agonist.[1] While other fibrates act predominantly as selective agonists for the PPARα subtype, Bezafibrate binds to and activates all three PPAR isotypes—alpha (

PPARα), gamma (PPARγ), and delta (PPARδ)—at comparable and clinically relevant concentrations.[1] This balanced, pan-agonist activity confers a multifaceted mechanism of action that extends beyond simple lipid modulation. It allows Bezafibrate to influence a complex network of metabolic and cellular processes, including glucose homeostasis, inflammation, endothelial function, and fibrinogen metabolism.[6]

This broad mechanism provides a compelling rationale for its observed clinical benefits, particularly in patient populations with complex metabolic disturbances. The activation of PPARα drives its potent lipid-modifying effects, consistent with its drug class. However, the concurrent activation of PPARγ, the same molecular target for the thiazolidinedione class of antidiabetic drugs, underpins its ability to improve insulin sensitivity and glycemic control.[6] This dual action on both lipid and glucose metabolism makes Bezafibrate a particularly logical therapeutic choice for patients with atherogenic dyslipidemia, a condition commonly associated with metabolic syndrome and type 2 diabetes, which is characterized by high triglycerides (TG), low HDL-C, and a predominance of small, dense low-density lipoprotein (LDL) particles.[3] Furthermore, its pleiotropic effects have spurred significant investigational interest in its use for other complex conditions, most notably as a promising off-label therapy for Primary Biliary Cholangitis (PBC) and as a potential treatment for rare mitochondrial disorders like Barth syndrome.[1] This report provides a comprehensive review of the physicochemical properties, pharmacology, clinical efficacy, safety profile, and therapeutic positioning of Bezafibrate.

Section 2: Physicochemical Properties and Formulations

The precise identification and characterization of a drug's physicochemical properties are fundamental to understanding its formulation, stability, and pharmacokinetic behavior. Bezafibrate is a synthetic, small molecule compound belonging to the fibrate class.[1]

Chemical Identification

Bezafibrate is a monocarboxylic acid amide, structurally derived from propionic acid and related to clofibrate.[11] It is formally produced by the condensation of the carboxy group of 4-chlorobenzoic acid with the amino group of 2-[4-(2-aminoethyl)phenoxy]-2-methylpropanoic acid.[11] Its key chemical identifiers are summarized in Table 2.1.

Table 2.1: Summary of Chemical and Physical Identifiers of Bezafibrate

Property	Value	Source(s)
IUPAC Name	2-(4-{2-[(4-chlorobenzoyl)amino]ethyl}phenoxy)-2-methylpropanoic acid	3
CAS Number	41859-67-0	3
Molecular Formula	C19​H20​ClNO4​	4
Molecular Weight	361.82 g/mol	3
Melting Point	186.00 °C	4
DrugBank ID	DB01393	1
FDA UNII	Y9449Q51XH	3

Physical Properties

Bezafibrate exists as a solid at room temperature.[11] Its solubility characteristics are critical for its formulation and oral bioavailability. It is characterized as being sparingly soluble or insoluble in water, with an estimated solubility of 1.224 mg/L at 25 °C.[4] This low aqueous solubility necessitates specific formulation strategies to ensure adequate absorption from the gastrointestinal tract. In contrast, it is soluble in organic solvents such as methanol and dimethylformamide (DMF).[15]

Formulations

To accommodate different dosing regimens and optimize patient adherence, Bezafibrate is commercially available in oral tablet form, primarily in two distinct formulations:

• Immediate-Release (IR) Tablets: These formulations typically contain 200 mg of the active ingredient and are designed for multiple daily administrations, usually three times per day, to maintain therapeutic plasma concentrations due to the drug's short intrinsic half-life.[1]
• Sustained-Release (SR) / Retard Tablets: These advanced formulations typically contain 400 mg of Bezafibrate and are engineered to release the drug over an extended period. This allows for convenient once-daily dosing, which can significantly improve patient compliance.[1] The SR formulation utilizes excipients such as hydroxypropyl methylcellulose and methacrylate polymers to control the rate of drug dissolution and absorption.[18]

Chemical Synthesis

The synthesis of Bezafibrate is a multi-step chemical process. A key step involves the reaction of the p-chlorobenzamide of tyramine with ethyl 2-bromo-2-methylpropionate via a Williamson ether synthesis. The resulting ester is subsequently hydrolyzed to yield the final carboxylic acid product.[3]

Section 3: Pharmacology

The clinical utility of Bezafibrate is rooted in its complex and multifaceted pharmacology. Unlike more selective agents, its ability to engage multiple nuclear receptor pathways results in a broad spectrum of effects on lipid metabolism, glucose homeostasis, and inflammatory processes.

3.1 Mechanism of Action

Primary Mechanism - Pan-PPAR Agonism

Bezafibrate's primary mechanism of action is its function as a direct agonist for all three subtypes of the Peroxisome Proliferator-Activated Receptors (PPARα, PPARγ, and PPARδ).[1] PPARs are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily.[19] Upon binding Bezafibrate, the receptor undergoes a conformational change, allowing it to form a heterodimer with another nuclear receptor, the Retinoid X Receptor (RXR). This Bezafibrate-PPAR-RXR complex then binds to specific DNA sequences known as Peroxisome Proliferator Response Elements (PPREs) in the promoter regions of target genes, thereby modulating their transcription.[19] The activation of each PPAR subtype contributes distinct and complementary effects to the drug's overall clinical profile.

• PPARα Activation: This is the canonical mechanism of action for all fibrate drugs and is central to Bezafibrate's lipid-modifying properties.[6] PPARα is highly expressed in tissues with high rates of fatty acid catabolism, such as the liver, heart, skeletal muscle, and kidney.[10] Its activation by Bezafibrate orchestrates a coordinated response to increase fatty acid oxidation and clear triglyceride-rich lipoproteins from the circulation. Key downstream effects include:
• Increased Lipoprotein Lipase (LPL) Activity: Upregulation of LPL, an enzyme located on the surface of capillaries, enhances the hydrolysis and clearance of triglycerides from VLDL (very-low-density lipoproteins) and chylomicrons.[2]
• Increased Fatty Acid Oxidation: Activation of genes encoding for enzymes involved in mitochondrial fatty acid β-oxidation, such as carnitine palmitoyltransferase I (CPT1), stimulates the breakdown of fatty acids within the liver and muscle. This reduces the intracellular pool of fatty acids available for the synthesis of new triglycerides.[6]
• Apolipoprotein Modulation: PPARα activation increases the hepatic expression of Apolipoprotein A-I (Apo A-I) and Apolipoprotein A-II (Apo A-II), the primary protein components of HDL particles, which contributes to the observed increase in HDL-C levels.[21] Conversely, it decreases the expression of Apolipoprotein C-III (Apo C-III), an inhibitor of LPL, further promoting triglyceride clearance.[22]
• PPARγ Activation: This component of Bezafibrate's action is crucial for its beneficial effects on glucose metabolism and distinguishes it from more selective fibrates.[23] PPARγ is most abundantly expressed in adipose tissue and plays a pivotal role in regulating adipogenesis, lipid storage, and insulin sensitivity.[7] Thiazolidinedione drugs, which are potent PPARγ agonists, are used as insulin sensitizers in the treatment of type 2 diabetes.[7] Bezafibrate's activation of PPARγ contributes to:
• Improved Insulin Sensitivity: By modulating gene expression in adipocytes, it helps to reduce circulating levels of free fatty acids, which are known to contribute to insulin resistance in muscle and liver tissue. This results in improved glucose tolerance and overall insulin sensitivity.[1]
• PPARδ Activation: This receptor is expressed in numerous tissues, including skeletal muscle, and is involved in the regulation of lipid metabolism and energy homeostasis.[6] Activation of PPARδ by Bezafibrate is associated with increased fatty acid oxidation in muscle tissue and enhanced overall energy expenditure, complementing the lipid-lowering effects mediated by PPARα.[6]

Bezafibrate is considered a balanced pan-agonist, as it activates all three human PPAR subtypes with comparable potency.[7] Reported half maximal effective concentrations (

EC50​) for the human receptors are approximately 20-50 µM for PPARα, 60 µM for PPARγ, and 20-40 µM for PPARδ.[1] This unique ability to modulate a triad of metabolic pathways simultaneously forms the mechanistic basis for its therapeutic efficacy in complex disorders like metabolic syndrome.

Pleiotropic Effects

Beyond its direct effects on lipid and glucose metabolism, Bezafibrate exerts several other potentially cardioprotective effects:

• Anti-inflammatory Action: PPAR activation is known to have anti-inflammatory consequences, which may contribute to the stabilization of atherosclerotic plaques.[6]
• Fibrinogen Reduction: Bezafibrate significantly reduces elevated plasma levels of fibrinogen, a key protein involved in blood coagulation and a determinant of blood viscosity. Elevated fibrinogen is an independent risk factor for cardiovascular events, and its reduction may confer an anti-thrombotic benefit.[5]
• Mitochondrial Function: Preclinical studies indicate that Bezafibrate can improve mitochondrial function, including increasing mitochondrial membrane potential and ATP levels.[1] This has led to its investigation in mitochondrial disorders like Barth syndrome.[1]
• Neuroinflammation and Neurogenesis: In animal models of depression, Bezafibrate has demonstrated antidepressant-like effects, which have been linked to the promotion of hippocampal neurogenesis and reduction of neuroinflammation via the PPARα/BDNF signaling pathway.[7]

3.2 A Novel Secondary Mechanism

While the pan-PPAR agonist model is well-established, compelling evidence from preclinical studies suggests a more nuanced, dose-dependent mechanism of action. A pivotal study using wild-type and Ppara-null mice revealed that the triglyceride-lowering effect of Bezafibrate may be mediated by different pathways depending on the administered dose.[27]

At high doses (100 mg/kg/day in mice), which are typical for rodent experiments but supra-physiological compared to human clinical doses, the triglyceride reduction was dependent on PPARα activation, as expected. This effect was absent in the Ppara-null mice.[27]

However, at clinically relevant low doses (10 mg/kg/day), Bezafibrate effectively lowered serum and liver triglycerides in both wild-type and Ppara-null mice. This demonstrates a PPARα-independent mechanism at therapeutic concentrations. The study identified this alternative pathway as the suppression of hepatic lipogenesis through the down-regulation of Sterol Regulatory Element-Binding Protein-1c (SREBP-1c), a master transcriptional regulator of fatty acid and triglyceride synthesis.[27]

This finding is of profound significance. It suggests that the clinical effects observed in humans may be a composite of two distinct actions: a PPARα-independent suppression of fat synthesis via SREBP-1c and a concomitant pan-PPAR-mediated increase in fat oxidation and clearance. This dual mechanism could have important implications for optimizing dosing strategies to maximize efficacy while potentially minimizing mechanism-based side effects. It challenges the long-held dogma that fibrate action is exclusively mediated by PPARα and opens new avenues for understanding the full therapeutic potential of Bezafibrate.

3.3 Pharmacodynamics

The integrated molecular actions of Bezafibrate translate into a distinct and beneficial pattern of pharmacodynamic effects in patients.

• Lipid Profile Modification: The hallmark effect of Bezafibrate therapy is a comprehensive improvement in the lipid profile. It produces a marked decrease in elevated triglyceride levels, a substantial and clinically significant increase in HDL-C levels, and a modest but consistent decrease in total cholesterol and LDL-cholesterol.[1] This profile is particularly effective in correcting the atherogenic dyslipidemia associated with insulin resistance and metabolic syndrome.[3]
• Glucose Metabolism: Consistent with its PPARγ activity, Bezafibrate improves markers of glycemic control. It has been shown to improve insulin sensitivity, reduce fasting and postprandial blood glucose levels, and significantly lower hemoglobin A1c (HbA1c) concentrations, particularly in patients with pre-existing impaired glucose tolerance or overt type 2 diabetes.[1] Clinical studies suggest that this effect may delay the progression from impaired glucose tolerance to new-onset diabetes.[3]
• Other Cardiovascular Risk Markers: Bezafibrate therapy leads to a reduction in elevated levels of two important non-lipid cardiovascular risk factors: fibrinogen and lipoprotein(a) [Lp(a)].[5] The reduction in fibrinogen lowers blood viscosity and may reduce thrombotic risk, while the lowering of Lp(a) addresses another independent genetic risk factor for atherosclerosis.[5]

Section 4: Pharmacokinetics (ADME)

The absorption, distribution, metabolism, and excretion (ADME) profile of Bezafibrate dictates its dosing regimen, potential for drug accumulation, and safety considerations in specific patient populations.

Absorption

Following oral administration, Bezafibrate is rapidly and almost completely absorbed from the gastrointestinal tract.[20] The time to reach maximum plasma concentration (

Tmax​) varies by formulation. For immediate-release (IR) tablets, Tmax​ is typically observed within 1 to 2 hours, whereas for the sustained-release (SR) formulation, this is extended to 3 to 4 hours.[2] The relative bioavailability of the 400 mg SR formulation is approximately 70% compared to the standard IR formulation.[26] Administration with or after a meal is recommended, as this can improve tolerability and may slow the rate of absorption.[17]

Distribution

Once in the systemic circulation, Bezafibrate is extensively bound to plasma proteins, primarily serum albumin, with a binding rate of 94-96%.[26] This high degree of protein binding means that only a small fraction of the drug is free (unbound) and pharmacologically active at any given time. The volume of distribution (

Vd​), a theoretical pharmacokinetic parameter that relates the amount of drug in the body to the concentration in the plasma, has not been explicitly defined for Bezafibrate in the available literature. This parameter is not a true physiological volume but rather an indicator of the extent of drug distribution into tissues relative to the plasma.[31]

Metabolism

Bezafibrate is primarily metabolized in the liver.[6] The principal metabolic pathway is conjugation with glucuronic acid to form bezafibrate glucuronide, a more water-soluble compound that is readily excreted by the kidneys.[6]

Excretion

The elimination of Bezafibrate and its metabolites is rapid and occurs almost exclusively through the renal route, with the majority of the dose being excreted in the urine.[12] The biological half-life (

T1/2​) of the parent compound is short, typically in the range of 1 to 2 hours for the standard formulation.[20] Some studies with single doses have reported a slightly longer half-life of approximately 2 to 2.3 hours.[1] This short half-life necessitates the three-times-daily dosing schedule for the IR formulation and provides the rationale for the development of the once-daily SR formulation.[12]

The near-total reliance on renal excretion is the most critical pharmacokinetic characteristic from a clinical safety perspective. In patients with normal renal function, the rapid elimination prevents drug accumulation during long-term therapy.[12] However, in patients with renal impairment, the elimination pathway is compromised, leading to a dramatic increase in the drug's half-life and plasma concentrations. For instance, in a patient with a creatinine clearance of only 13 ml/min, the half-life was observed to be 20.1 hours—a tenfold increase compared to healthy volunteers.[34] This accumulation is directly linked to an increased risk of toxicity, most notably severe myopathy and rhabdomyolysis. This pharmacokinetic principle is the foundation for the stringent requirements for dose adjustment and the contraindications for Bezafibrate use in patients with significant renal dysfunction.[10]

The table below summarizes key pharmacokinetic parameters observed in human studies after single oral doses.

Table 4.1: Summary of Pharmacokinetic Parameters of Bezafibrate Across Different Doses

Dose (mg)	Formulation	Population	Cmax (μg/mL)	AUC (μg·h/mL)	T1/2 (h)	Source(s)
100	Single, Oral	Human Plasma	1.8 - 2.06	7.41 - 8.02	1.9 - 2.0	1
200	Single, Oral	Human Plasma	3.46 - 3.75	13.27 - 15.37	2.3	1
300	Single, Oral	Human Plasma	16.3	69.4 - 256.5	Not Available	1
200	Multiple, Oral	Human	1.7	5.2	Not Available	27
300	Multiple, Oral	Human	10.5	39.0	Not Available	27
400	Multiple, Oral	Human	4.9	18.1	Not Available	27

Note: AUC and Cmax values can vary significantly between studies due to differences in analytical methods, populations, and formulations.

Section 5: Clinical Efficacy and Therapeutic Applications

Bezafibrate's broad pharmacological profile has established its utility in a range of metabolic disorders, from its traditional role in managing hyperlipidemia to emerging applications in cholestatic liver disease and other complex conditions.

5.1 Approved and Primary Indications

The primary and approved use of Bezafibrate is as an adjunct to diet and other non-pharmacological therapies for the management of hyperlipidemia.[28]

• Primary Hyperlipidemias: It is indicated for the treatment of most forms of primary hyperlipidemia, including Fredrickson classification types IIa (hypercholesterolemia), IIb (combined hyperlipidemia), III (dysbetalipoproteinemia), IV (hypertriglyceridemia), and V (mixed hypertriglyceridemia).[28] Clinical evidence demonstrates that it is of greatest therapeutic benefit in conditions predominantly featuring hypertriglyceridemia and/or low levels of HDL-C.[5]
• Secondary Dyslipidemias: Bezafibrate is also effective in treating dyslipidemias that are secondary to other underlying medical conditions. It is considered a logical therapeutic choice for patients with dyslipidemia associated with non-insulin-dependent diabetes mellitus (NIDDM) and metabolic syndrome.[5] In this population, its unique ability to concurrently improve the lipid profile and enhance glycemic control provides a distinct advantage over other lipid-lowering agents.[3]

5.2 Off-Label and Investigational Uses

The pleiotropic effects of Bezafibrate, stemming from its pan-PPAR agonism, have prompted significant research into its use beyond lipid management. This has led to a notable repositioning of the drug from a legacy cardiovascular agent to a potential therapy for complex metabolic and inflammatory diseases.

• Primary Biliary Cholangitis (PBC): One of the most significant emerging applications for Bezafibrate is in the treatment of PBC, a chronic autoimmune cholestatic liver disease.[38] It is now widely used off-label, typically as an add-on therapy for patients who have an inadequate biochemical response to the standard first-line treatment, ursodeoxycholic acid (UDCA).[10] Clinical experience and studies have shown that Bezafibrate can lead to significant improvements in serum markers of cholestasis and liver injury, including alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST).[9] Furthermore, it has been reported to effectively alleviate pruritus (itching), a debilitating symptom for many PBC patients.[9] The mechanism in PBC is thought to be multifactorial, involving anti-inflammatory, anti-fibrotic, and anti-cholestatic effects mediated by its pan-PPAR activity.[10] The promise of this application is underscored by the initiation of formal, industry-sponsored Phase 2 clinical trials by Intercept Pharmaceuticals, which are investigating a fixed-dose combination of Bezafibrate and another liver-targeted drug, obeticholic acid (OCA), for PBC.[39] This represents a critical step toward potential regulatory approval for a major new indication.
• Barth Syndrome: Bezafibrate has received an orphan drug designation from the U.S. Food and Drug Administration (FDA) for the therapeutic treatment of Barth syndrome.[1] Barth syndrome is a rare, X-linked genetic disorder characterized by cardiomyopathy, skeletal myopathy, neutropenia, and growth delay, caused by defects in mitochondrial lipid metabolism. The orphan designation is likely based on Bezafibrate's known ability to stimulate mitochondrial fatty acid oxidation and improve mitochondrial function, as demonstrated in preclinical models.[1]
• Neurodegenerative and Psychiatric Disorders: Preclinical research has uncovered potential neurological benefits. In transgenic mouse models of tauopathy, a key feature of Alzheimer's disease, Bezafibrate was shown to reduce the hyperphosphorylation of tau protein.[3] In separate animal models of depression, Bezafibrate administration demonstrated significant antidepressant-like activity, an effect potentially mediated through the PPARα/BDNF signaling pathway in the hippocampus, which is involved in neurogenesis and mood regulation.[7]
• Oncology: Preliminary research from the University of Birmingham has suggested that a combination of Bezafibrate and the contraceptive steroid medroxyprogesterone acetate could represent a novel, non-toxic treatment strategy for a range of cancers.[3]
• Hepatitis C: An Australian biotechnology company, Giaconda, has explored a combination therapy named Hepaconda, which pairs Bezafibrate with chenodeoxycholic acid, for the treatment of hepatitis C infection.[3]

These investigational avenues highlight a paradigm shift in the perception of Bezafibrate. Its success, particularly in the context of PBC, could revitalize broader clinical and research interest in pan-PPAR agonists as a therapeutic class for a variety of orphan metabolic and inflammatory diseases, extending their utility far beyond the traditional domain of cardiovascular risk reduction.

Section 6: Dosage, Administration, and Monitoring

The safe and effective use of Bezafibrate requires adherence to appropriate dosing schedules, administration protocols, and a robust monitoring plan to assess efficacy and mitigate potential adverse effects.

Standard Dosing

The recommended dosage of Bezafibrate depends on the formulation used:

• Immediate-Release (IR) Formulation: The standard adult dose is 200 mg taken three times daily (TID), for a total daily dose of 600 mg.[1]
• Sustained-Release (SR) Formulation: The standard adult dose is a single 400 mg tablet taken once daily (OD).[1]

Administration

To optimize absorption and minimize gastrointestinal side effects, Bezafibrate should be administered with or immediately after a meal.[17] The tablets, particularly the sustained-release formulation, must be swallowed whole with a sufficient amount of fluid and should not be chewed, crushed, or broken, as this would disrupt the controlled-release mechanism and could lead to dose dumping.[17]

Dose Adjustments in Renal Impairment

Given that Bezafibrate is eliminated almost exclusively by the kidneys, its use in patients with renal impairment necessitates careful dose adjustments to prevent drug accumulation and toxicity. Renal function should be assessed at baseline before initiating therapy.

• The 400 mg sustained-release formulation is contraindicated in patients with a creatinine clearance (CrCl) below 60 mL/min.[10]
• For patients with mild to moderate renal impairment, only the immediate-release formulation should be used, with the dosage and frequency adjusted according to the degree of impairment. The following table provides a general guideline for dosing based on renal function.

Table 6.1: Dosing Guidelines for Bezafibrate in Renal Impairment

Glomerular Filtration Rate (GFR) / Creatinine Clearance (CrCl) (mL/min)	Recommended Dose and Formulation	Source(s)
> 60	Standard dose: 200 mg TID (IR) or 400 mg OD (SR)	37
40 - 60	400 mg daily (using 200 mg IR tablets)	35
15 - 40	200 mg (IR) every 24–48 hours	35
< 15	Use is contraindicated / Avoid	35
Patients on Dialysis	Use is contraindicated	16

Note: Dosing recommendations may vary slightly by jurisdiction. Clinicians should consult local prescribing information.

Essential Monitoring

Regular laboratory monitoring is crucial for all patients receiving Bezafibrate therapy.

• Lipid Panel: Periodic measurement of total cholesterol, LDL-C, HDL-C, and triglycerides is necessary to evaluate the therapeutic efficacy of the drug.[29]
• Liver Function Tests (LFTs): Baseline and periodic monitoring of liver transaminases (ALT and AST) is required to detect potential hepatotoxicity.[2]
• Creatine Phosphokinase (CPK): Baseline and periodic monitoring of CPK levels is recommended, particularly in patients at high risk for myopathy. This includes those with renal impairment, those taking concomitant statins, or any patient who reports unexplained muscle pain, tenderness, or weakness.[44]
• Renal Function: Serum creatinine and/or calculated creatinine clearance should be monitored periodically, as a decline in renal function necessitates dose adjustment or discontinuation.[2]
• Complete Blood Count (CBC): Periodic blood counts are recommended, especially during the first 12 months of treatment, due to rare reports of mild decreases in hemoglobin, white blood cells, or platelets.[18]

Section 7: Safety Profile and Tolerability

Bezafibrate is generally well-tolerated, with a safety profile established over several decades of clinical use.[1] However, like all fibrates, it is associated with a risk of specific adverse effects that require careful monitoring and patient counseling.

7.1 Adverse Effects

Adverse effects associated with Bezafibrate can be categorized by their frequency and severity.

Common Adverse Effects

These effects are typically mild to moderate in severity, often occur at the beginning of therapy, and may resolve as the body adjusts to the medication.

• Gastrointestinal Disturbances: This is the most frequently reported category of side effects and includes decreased appetite (anorexia), nausea, heartburn, gastric or abdominal pain, diarrhea, and constipation.[2]
• Neurological Effects: Headache and dizziness are commonly reported.[20]
• Dermatological Reactions: Mild skin reactions such as rash, pruritus (itching), and urticaria (hives) may occur.[46]

Serious Adverse Effects

These events are less common to rare but can be severe and require immediate medical attention.

• Myopathy and Rhabdomyolysis: This is the most significant serious adverse effect associated with the fibrate class. Patients may experience myalgia (muscle pain), muscle cramps, or weakness (myasthenia).[16] In rare instances, this can progress to rhabdomyolysis, a severe condition involving the rapid breakdown of skeletal muscle tissue. The release of muscle contents, particularly myoglobin, into the bloodstream can lead to acute kidney injury and renal failure.[1] The risk of myopathy and rhabdomyolysis is substantially increased in certain high-risk groups, including patients with pre-existing renal impairment, those receiving excessive dosages, and those taking concomitant medications known to increase myotoxicity, such as statins.[2]
• Hepatotoxicity: Bezafibrate can cause elevations in liver transaminases (ALT, AST), which are usually asymptomatic and reversible upon discontinuation of the drug.[46] However, regular monitoring is essential. Serious liver injury, manifesting with symptoms such as jaundice (yellowing of the skin or eyes), dark urine, severe fatigue, and abdominal pain, is a rare but serious event.[9]
• Cholelithiasis (Gallstones): Fibrates, including Bezafibrate, increase the cholesterol saturation of bile. This alteration in bile composition increases the lithogenicity of bile and elevates the risk of developing cholesterol gallstones.[29]
• Photosensitivity: Some individuals may develop photoallergic or phototoxic reactions, where the skin becomes abnormally sensitive to sunlight, leading to exaggerated sunburn-like symptoms upon exposure.[46]
• Hematologic Changes: Rare cases of mild decreases in hemoglobin (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia) have been documented.[1]
• Severe Allergic Reactions: Anaphylactoid reactions, though rare, can occur and are a medical emergency. Symptoms include severe rash, hives, difficulty breathing or swallowing, and swelling of the face, lips, tongue, or throat.[9]

7.2 Contraindications and Precautions

To ensure patient safety, the use of Bezafibrate is contraindicated in several specific populations and conditions.

Absolute Contraindications

• Known hypersensitivity or allergy to Bezafibrate, any of its excipients, or other fibrate drugs.[2]
• Severe hepatic impairment, including primary biliary cirrhosis (in some jurisdictions), or persistent, unexplained elevations in liver function tests.[35]
• Severe renal impairment (e.g., CrCl < 15 mL/min) or patients undergoing dialysis.[16] The 400 mg SR formulation is specifically contraindicated in patients with a CrCl < 60 mL/min.[37]
• Pre-existing gallbladder disease (with or without cholelithiasis).[29]
• A history of photoallergic or phototoxic reactions to any fibrate drug.[36]
• Pregnancy and lactation.[2]

Precautions

• Mild to Moderate Renal or Hepatic Impairment: Use with caution and with appropriate dose adjustments and enhanced monitoring.[2]
• Concomitant Statin Use: This combination significantly increases the risk of myopathy and requires very close monitoring of muscle symptoms and CPK levels.[9]
• High-Risk Patients: Caution is advised in patients with conditions that may predispose them to adverse effects, such as uncontrolled type 2 diabetes, hypoalbuminemia (as seen in nephrotic syndrome), or a history of alcohol abuse.[2]

7.3 Drug-Drug Interactions

Bezafibrate has several clinically significant drug-drug interactions that can alter its efficacy or increase the risk of toxicity.

Table 7.1: Clinically Significant Drug-Drug Interactions with Bezafibrate

Interacting Drug/Class	Potential Effect	Clinical Management/Recommendation	Source(s)
HMG-CoA Reductase Inhibitors (Statins)	Pharmacodynamic interaction: Increased risk of myopathy, myositis, and rhabdomyolysis.	Combination should be used with extreme caution. Closely monitor for muscle pain/weakness and check CPK levels. Avoid in patients with predisposing factors for myopathy.	30
Coumarin Anticoagulants (e.g., Warfarin, Acenocoumarol)	Pharmacodynamic interaction: Bezafibrate potentiates the anticoagulant effect, increasing the risk of bleeding.	Monitor INR closely upon initiation, dose adjustment, or discontinuation of Bezafibrate. A reduction in the anticoagulant dose is often required.	26
Bile Acid Sequestrants (e.g., Cholestyramine, Colestipol)	Pharmacokinetic interaction: Sequestrants bind to Bezafibrate in the gut, impairing its absorption.	Administer Bezafibrate at least 1 hour before or 4-6 hours after the sequestrant. A common recommendation is to separate doses by at least 2 hours.	29
Sulfonylureas & Insulin	Pharmacodynamic interaction: Bezafibrate can enhance the glucose-lowering effect of these agents.	Increased risk of hypoglycemia. Monitor blood glucose levels closely, especially when initiating Bezafibrate therapy. Dose adjustment of the antidiabetic agent may be necessary.	42
Cyclosporine	Potential for interaction, mechanism not fully defined.	Use with caution and monitor renal function and cyclosporine levels.	30
MAO Inhibitors	Potential for severe interactions.	Concurrent use is contraindicated.	42
CYP2C8 Substrates	Pharmacokinetic interaction: Bezafibrate is an inhibitor of the CYP2C8 enzyme.	May increase plasma concentrations and toxicity of drugs metabolized by CYP2C8 (e.g., repaglinide, paclitaxel). Use with caution.	50

Section 8: Use in Specific Populations

The use of Bezafibrate in certain populations requires special consideration due to altered pharmacokinetics, increased risk of adverse events, or a lack of safety data.

Geriatric Patients

The use of Bezafibrate in elderly patients is a significant area of concern and is often restricted. Many prescribing guidelines recommend avoiding its use in individuals over the age of 70.[2] This recommendation is not arbitrary but is grounded in a direct clinical application of the drug's core pharmacokinetic properties. Bezafibrate is eliminated almost exclusively by the kidneys.[34] It is a well-established physiological fact that renal function, specifically the glomerular filtration rate (GFR), naturally declines with age.[43] In elderly individuals, this reduced renal clearance leads to impaired elimination of Bezafibrate, resulting in a significantly prolonged half-life and drug accumulation.[34] This accumulation is a primary risk factor for the development of severe myopathy and rhabdomyolysis.[5] Therefore, the age-based restriction serves as a pragmatic safety measure to protect a population in which the creatinine clearance is highly likely to be below the safety threshold of 60 mL/min, even if it has not been formally measured.[2] If Bezafibrate is deemed essential for an elderly patient, its use must be guided by a calculated creatinine clearance (e.g., using the Cockcroft-Gault equation), not by age or serum creatinine alone, and the dose must be appropriately reduced.[16]

Pediatric Patients

The safety and efficacy of Bezafibrate in children and adolescents have not been well-established, and its use in this population is very limited.[2] Some sources provide a potential oral dosage of 200 mg/day for adolescents or a weight-based dose of 10-20 mg/kg/day (maximum 400 mg) for children and adolescents with dyslipidemia.[35] However, it should only be prescribed in this age group if a specialist determines that the potential benefits significantly outweigh the substantial unknown risks. If used, the patient must be monitored very closely for any adverse effects.[2]

Pregnancy and Lactation

Pregnancy

Bezafibrate is contraindicated for use during pregnancy.[36] There is very limited human data regarding its safety in pregnant women, and potential risks to the fetus cannot be excluded.[2] Dyslipidemia is not typically a condition that requires urgent treatment during pregnancy. Therefore, therapy is generally deferred until after delivery. Patients of childbearing potential who are taking Bezafibrate should be advised to use a reliable method of contraception.[29] If a patient is planning to become pregnant, it may be advisable to discontinue the drug several months in advance after consultation with their physician.[29] A single case report has been published describing the successful use of a combination of UDCA and Bezafibrate to treat a new diagnosis of Primary Biliary Cholangitis that presented during pregnancy, but this represents an exceptional circumstance managed under specialist care.[51]

Lactation

Bezafibrate is also contraindicated during breastfeeding.[2] It is not known whether Bezafibrate or its metabolites are excreted into human breast milk. Due to the lack of safety data and the potential for adverse effects in the nursing infant, breastfeeding is not recommended while taking this medication.[2]

Section 9: Comparative Analysis and Therapeutic Positioning

To fully appreciate the clinical role of Bezafibrate, it is essential to compare it with other fibrates and understand its specific place within current therapeutic guidelines for managing dyslipidemia.

Comparison with Other Fibrates (Fenofibrate and Gemfibrozil)

Bezafibrate, fenofibrate, and gemfibrozil are the most commonly used fibrates, but they possess distinct pharmacological and clinical profiles.

• Mechanism of Action: The most fundamental difference lies in their interaction with PPARs. While gemfibrozil and fenofibrate are considered relatively selective PPARα agonists, Bezafibrate is a pan-PPAR agonist, activating PPARα, PPARγ, and PPARδ.[3] This broader mechanism is the source of its unique clinical effects, particularly on glucose metabolism.
• Clinical Efficacy:
• Triglycerides and LDL-C: All three fibrates are potent triglyceride-lowering agents, typically reducing levels by 30-50%.[8] Head-to-head and switching studies suggest that the effects of Bezafibrate and fenofibrate on triglyceride and LDL-C levels are largely comparable.[23] Gemfibrozil may have a more neutral effect on LDL-C levels.[8]
• HDL-C: Bezafibrate appears to exert a more favorable and significant increasing effect on HDL-C levels compared to fenofibrate.[23]
• Glucose Metabolism: This is where Bezafibrate demonstrates a clear clinical advantage. Due to its PPARγ agonism, Bezafibrate significantly improves glycemic control, as evidenced by reductions in HbA1c, an effect not consistently observed with the more selective PPARα agonist fenofibrate.[3] This makes Bezafibrate a superior choice for patients with concurrent dyslipidemia and impaired glucose metabolism.
• Safety and Drug Interactions:
• Statin Combination Therapy: The risk of myopathy is a major concern when combining any fibrate with a statin. However, the risk is not uniform across the class. Gemfibrozil significantly increases the risk because it inhibits the glucuronidation pathway (specifically via UGT enzymes) responsible for metabolizing many statins, leading to elevated statin plasma levels.[48] In contrast, fenofibrate and Bezafibrate do not appear to have this significant pharmacokinetic interaction, making them the preferred fibrates for combination therapy with statins when clinically indicated.[8]
• Overall Tolerability: In an observational study conducted in New Zealand comparing the drugs in normal clinical practice, gemfibrozil was found to be less effective and was associated with a higher rate of treatment withdrawal due to adverse effects when compared to Bezafibrate.[54]

The following table provides a comparative summary of the three fibrates.

Table 9.1: Comparative Profile of Bezafibrate, Fenofibrate, and Gemfibrozil

Feature	Bezafibrate	Fenofibrate	Gemfibrozil
Primary Mechanism	Pan-PPAR Agonist (PPARα,γ,δ)	Selective PPARα Agonist	Selective PPARα Agonist
Efficacy on Triglycerides	High (↓↓↓)	High (↓↓↓)	High (↓↓↓)
Efficacy on HDL-C	High (↑↑↑)	Moderate (↑↑)	Moderate (↑↑)
Efficacy on LDL-C	Modest (↓)	Modest (↓)	Neutral to Modest (↔/↓)
Effect on Glucose/HbA1c	Significant Improvement (↓↓)	Minimal to None	Minimal to None
Myopathy Risk with Statins	Lower (vs. Gemfibrozil)	Lower (vs. Gemfibrozil)	Higher (Pharmacokinetic Interaction)
Primary Elimination Route	Renal	Renal	Renal (after hepatic metabolism)

Therapeutic Positioning

The role of fibrates in the modern era of lipid management, which is dominated by statins, is a subject of ongoing discussion.

• General Guideline Positioning: Current major guidelines, such as those from the National Cholesterol Education Program (NCEP) and the American Diabetes Association (ADA), prioritize LDL-C reduction as the primary target of therapy, making statins the unequivocal first-line agents for cardiovascular risk reduction.[8] Fibrates, including Bezafibrate, are generally positioned as second-line therapy.[8]
• European Regulatory Position: The European Medicines Agency (EMA) has taken a more restrictive stance, recommending that fibrates should only be used in patients for whom statins are contraindicated or not tolerated.[55]
• Specific Niche for Bezafibrate: Despite these general recommendations, Bezafibrate occupies a crucial therapeutic niche. Its ideal clinical application is in the treatment of patients presenting with atherogenic dyslipidemia in the context of metabolic syndrome or overt type 2 diabetes.[3] For this high-risk population, statin monotherapy often fails to adequately address the high triglyceride and low HDL-C components of their dyslipidemia. Bezafibrate's unique pan-PPAR mechanism, which allows it to simultaneously correct the lipid abnormalities (via PPARα/δ) and improve insulin sensitivity and glycemic control (via PPARγ), makes it a highly logical and mechanistically sound choice.[23]
• Combination Therapy: In patients with severe mixed dyslipidemia who do not achieve their lipid goals on statin monotherapy, the addition of Bezafibrate can be a valuable strategy. While this combination increases the risk of myopathy and requires diligent monitoring, the risk is considered lower than with gemfibrozil, making Bezafibrate a more appropriate partner for statins in this setting.[5]

Section 10: Regulatory Status and Commercial Landscape

The regulatory approval and market availability of Bezafibrate vary significantly across different global regions, reflecting its long history and evolving therapeutic role.

Regulatory Status

• United States (FDA): Bezafibrate is not approved by the U.S. Food and Drug Administration for the treatment of hyperlipidemia and is therefore not commercially available for this indication.[55] It is listed as a bulk ingredient available for animal drug compounding.[57] However, it has been granted two orphan drug designations by the FDA: one for the therapeutic treatment of Barth syndrome (designated in 2013) and another for the treatment of Primary Biliary Cholangitis.[1] These designations are intended to facilitate the development of drugs for rare diseases but do not constitute marketing approval.
• Europe (EMA): Bezafibrate has been approved and available in many European countries since 1977.[58] However, in 2010, the EMA's Committee for Medicinal Products for Human Use (CHMP) conducted a review of the fibrate class and concluded that their benefits in cardiovascular risk reduction were less robust than those of statins. Consequently, the CHMP recommended that the use of all fibrates, including Bezafibrate, be restricted to a second-line role for patients in whom statins are contraindicated or not tolerated.[55]
• Other Regions: Bezafibrate is widely approved and extensively used in many other parts of the world. It is available in Canada, Japan, and numerous countries throughout Asia, Latin America, and Africa, where it remains an important tool for managing dyslipidemia.[59]

Commercial Landscape

Reflecting its long-standing presence and post-patent status, Bezafibrate is produced by numerous pharmaceutical companies and marketed under a vast array of brand names globally.

• Manufacturers: While originally developed by Boehringer Mannheim, the active pharmaceutical ingredient (API) and finished formulations are now produced by a wide range of manufacturers.[3] Key global suppliers of the API include Sumitomo Chemical (Japan) and F. Hoffmann-La Roche (Switzerland).[61] Many other companies, such as Taj Pharmaceuticals (India), are major producers of generic Bezafibrate for global markets.[62]
• International Brand Names: The widespread availability of Bezafibrate is evident from the extensive list of international brand names under which it is sold. Some of the most prominent and widely recognized brands include:
• Bezalip / Bezalip SR / Bezalip Retard: This is perhaps the most common trade name, marketed by companies including Actavis, Roche, and Sandoz in countries across Europe, Asia, Latin America, and Canada.[3]
• Cedur: Marketed by companies such as Glenmark and Aurobindo in Brazil and parts of Europe.[58]
• Eulitop: Another brand from Aurobindo, available in Spain and other European countries.[58]
• Befizal: Marketed by Arrow in France.[58]
• Bezatol SR: The brand name used by Kissei Pharmaceutical in Japan.[1]

In addition to these, a multitude of other local and generic brand names exist, such as Befibrat (Germany), Bezacur (Argentina), Fibrazate XL (United Kingdom), and Norlip (Israel), underscoring its status as a widely accessible and affordable medication in many parts of the world.[59]

Section 11: Conclusion and Future Directions

Bezafibrate is a fibric acid derivative with a rich history spanning over four decades of clinical application. It has firmly established its role as an effective agent for the management of hyperlipidemia, particularly forms characterized by elevated triglycerides and low HDL-cholesterol. Its primary distinguishing feature is its unique mechanism of action as a balanced, pan-PPAR agonist. This ability to activate all three PPAR subtypes (PPARα, PPARγ, and PPARδ) provides a broader spectrum of metabolic benefits than more selective fibrates, most notably conferring a significant and clinically relevant improvement in glucose homeostasis and insulin sensitivity. This makes Bezafibrate a particularly valuable therapeutic option for the high-risk population of patients with atherogenic dyslipidemia co-existing with metabolic syndrome or type 2 diabetes.

The drug's safety profile is well-characterized and generally favorable. The most common adverse effects are mild gastrointestinal disturbances, while the most serious risks—myopathy and rhabdomyolysis—are rare but significant. These risks are critically linked to the drug's pharmacokinetic profile, specifically its near-exclusive renal elimination. This property mandates cautious use, strict dose adjustments, or outright contraindication in patients with impaired renal function and in the elderly, for whom a physiological decline in renal function is expected. Appropriate patient selection, dosing based on renal function, and diligent monitoring of liver enzymes and CPK are paramount to ensuring its safe use.

While its role in primary cardiovascular prevention has been largely superseded by statins, the future of Bezafibrate appears to lie in its strategic repositioning for new and complex therapeutic indications. The most promising of these is the treatment of Primary Biliary Cholangitis (PBC). Supported by strong mechanistic rationale and encouraging clinical data, Bezafibrate is being formally investigated in Phase 2 trials as a combination therapy for PBC patients with an inadequate response to standard treatment. A successful outcome in these trials could lead to the first major new regulatory approval for Bezafibrate in decades, potentially transforming the management paradigm for this chronic liver disease. Furthermore, early preclinical findings related to its potential neuroprotective, anti-inflammatory, and mitochondrial-enhancing properties suggest that additional therapeutic roles for this multifaceted and versatile drug may yet be uncovered, ensuring its continued relevance in modern medicine.

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