The Influence of Fed State Lipolysis Inhibition on the Intraluminal Behaviour and Absorption of Fenofibrate from a Lipid-Based Formulation

The bioavailability of lipophilic drugs may or may not be increased when administered with food due to increased solubilisation in fed state gastrointestinal (GI) fluids. The in vivo interplay between drug solubilisation, lipid phase digestion and drug absorption is complex and remains poorly understood. This study aimed to investigate the role of fed state GI lipolysis on the intraluminal behaviour and absorption of fenofibrate, formulated as the lipid-based formulation Fenogal. Therefore, a crossover study was performed in healthy volunteers using orlistat as lipase inhibitor. Fenofibrate concentrations were determined in the proximal jejunum and linked to simultaneously assessed systemic fenofibric acid concentrations. Inhibition of lipolysis by orlistat resulted in a faster onset of absorption in 4 out of 6 volunteers, reflected by a decrease in systemic Tmax between 20 and 140 min. In addition, the increase of undigested lipids present in the small intestine upon orlistat co-administration sustained drug solubilisation for a longer period, resulting in higher fenofibrate concentrations in the jejunum and improved absorption in 5 out of 6 volunteers (median AUC0–8h 8377 vs. 5832 μM.min). Sustaining drug solubilisation in the lipid phase may thus contribute to the absorption of lipophilic drugs. More research into the different mechanisms underlying lipophilic drug absorption from fed state media at different levels of digestion is warranted.

Peroxisome Proliferator-Activated Receptor α Activation Protects Retinal Ganglion Cells in Ischemia-Reperfusion Retinas

Background and Objective: Retinal ischemia-reperfusion (IR) leads to massive loss of retinal ganglion cells (RGC) and characterizes several blind-causing ophthalmic diseases. However, the mechanism related to retinal IR is controversial, and a drug that could prevent the RGC loss caused by IR is still lacking. This study aimed to investigate the role of endogenous retinal peroxisome proliferator-activated receptor (PPAR)α and the therapeutic effect of its agonist, fenofibric acid (FA), in IR-related retinopathy.Materials and Methods: Fenofibric acid treatment was applied to the Sprague–Dawley rats with IR and retinal cell line 28 cells with oxygen-glucose deprivation (OGD) (an in vitro model of IR). Western blotting, real-time PCR, and immunofluorescence were used to examine the expression levels of PPARα, glial fibrillary acidic protein (GFAP), and cyclooxygenase-2 (COX2). Hematoxylin and eosin (HE) staining, propidium iodide (PI) staining, retrograde tracing, and flash visual-evoked potential (FVEP) were applied to assess RGC injury and visual function.Results: Retinal IR down-regulated PPARα expression in vitro and in vivo. Peroxisome proliferator-activated receptor α activation by FA promoted survival of RGCs, mitigated thinning of the ganglion cell complex, and decreased the latency of positive waves of FVEPs after IR injury. Further, FA treatment enhanced the expression of endogenous PPARα and suppressed the expression of GFAP and COX2 significantly.Conclusion: Peroxisome proliferator-activated receptor α activation by FA is protective against RGC loss in retinal IR condition, which may occur by restoring PPARα expression, inhibiting activation of glial cells, and suppressing retinal inflammation. All these findings indicate the translational potential of FA in treating IR-related retinopathy.

Eco-Friendly Separation of Antihyperlipidemic Combination Using UHPLC Particle-Packed and Monolithic Columns by Applying Green Analytical Chemistry Principles

Efficient separation of pharmaceuticals and metabolites with the adequate resolution is a key factor in choosing the most suitable chromatographic method. For quality control, the analysis time is a key factor, especially in pharmacokinetic studies. High back pressure is considered as one of the most important factors in chromatography’s flow control, especially in UHPLC. The separation of the anti-hyperlipidemic mixtures was carried out using two columns: a column silica-based particle packed UHPLC and a monolithic column. The systematic suitability of the two columns was compared for the separation of Fenofibrate, its active metabolite, Fenofibric acid and Pravastatin using Atorvastatin as an internal standard. Separation on both columns was obtained using ethanol: buffer potassium dihydrogen orthophosphate pH = 3 (adjusted with orthophosphoric acid) (75:25 v/v) as mobile phase and flow rate 0.8 mL/min. The analytes’ peak detection was achieved by using a PDA detector at 287 nm, 214 nm, 236 nm, and 250 nm for Fenofibrate, Fenofibric acid, Pravastatin, and Atorvastatin, respectively. Reduction of back-pressure was achieved with the monolithic column, where the analytes could be completely separated in less than 1.5 min at a flow rate of 5 mL/min. The principles of Green Analytical Chemistry (GAC) were followed throughout the developed method using environmentally safe solvents.

STABILITY INDICATIVE AND COST EFFECTIVE ANALYTICAL METHOD DEVELOPMENT AND VALIDATION OF FENOFIBRIC ACID AND PITAVASTATIN BY USING RP-HPLC

Objective: The current investigation was pointed at developing and progressively validating novel, simple, responsive and stable RP-HPLC method for the measurement of active pharmaceutical ingredients of Fenofibric acid and Pitavastatin. Methods: A simple, selective, validated and well-defined stability that shows gradient RP-HPLC methodology for the quantitative determination of Fenofibric acid and Pitavastatin. The chromatographic strategy utilized X-bridge phenyl column of dimensions 250x4.6 mm, 5 micron, using isocratic elution with a mobile phase of acetonitrile and 0.1 percent formic acid (60:40). A flow rate of 1 ml/min and a detector wavelength of 242 nm utilizing the PDA detector were given in the instrumental settings. Results: Validation of the proposed method was carried out according to an international conference on harmonization (ICH) guidelines. LOD and LOQ for the two active ingredients were established with respect to test concentration. The calibration charts plotted were linear with a regression coefficient of R2 > 0.999, means the linearity was within the limit. Recovery, specificity, linearity, accuracy, robustness, ruggedness were determined as a part of method validation and the results were found to be within the acceptable range. Conclusion: The proposed method to be fast, simple, feasible and affordable in assay condition. During stability tests, it can be used for routine analysis of the selected drugs.

The Hyperlipidaemic Drug Fenofibrate Significantly Reduces Infection by SARS-CoV-2 in Cell Culture Models

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has caused a significant number of fatalities and worldwide disruption. To identify drugs to repurpose to treat SARS-CoV-2 infections, we established a screen to measure the dimerization of angiotensin-converting enzyme 2 (ACE2), the primary receptor for the virus. This screen identified fenofibric acid, the active metabolite of fenofibrate. Fenofibric acid also destabilized the receptor-binding domain (RBD) of the viral spike protein and inhibited RBD binding to ACE2 in enzyme-linked immunosorbent assay (ELISA) and whole cell-binding assays. Fenofibrate and fenofibric acid were tested by two independent laboratories measuring infection of cultured Vero cells using two different SARS-CoV-2 isolates. In both settings at drug concentrations, which are clinically achievable, fenofibrate and fenofibric acid reduced viral infection by up to 70%. Together with its extensive history of clinical use and its relatively good safety profile, this study identifies fenofibrate as a potential therapeutic agent requiring an urgent clinical evaluation to treat SARS-CoV-2 infection.

A Comprehensive Review on the Drug: Fenofibrate

Fenofibrate is currently used as antihyperlipidemic drug, which has a direct effect on lowering cholesterol, triglycerides and LDL (Low-Density Lipids), VLDL (Very Low-Density Lipids) levels along with raising the level of HDL (High-density Lipids) in the blood. It also plays a significant role in insulin resistance metabolic disorder. This drug is mainly used for controlling diseases related to lipids like hypercholesterolemia, severe hypertriglyceridemia and dyslipidaemia. Along with statins, it significantly controls the level of hypercholesterolemia and hypertriglyceridemia. It belongs to the group of drugs called 'Fibrate'. Fenofibrate was patented in 1969. In 1974, it was synthesized as a derivative of clofibrate and launched at the French market. It was marketed in 1975. In 2017, it was available as a generic medicine. Presently this API is being marketed in around 85 countries all over the world. Fenofibrate is a BCS Class-II drug having poor water solubility. The poor aqueous solubility of this drug causes low bioavailability and limited permeability through the GIT membrane. This API degrades at higher temperatures and in a humid environment, with one of the resultant degradation products being fenofibric acid. In the present review, we have discussed the historical development, pharmacology, analytical profile with its physicochemical properties and ongoing research scenario on this API.

NOVEL RPHPLC-PDA METHOD FOR SIMULTANEOUS ESTIMATION OF HEPARIN AND ITS CO-ADMINISTERED DRUG (FENOFIBRIC ACID) IN MIXTURE

The poly prescription and co-administration of more than two drugs to treat patients for the disease conditions are inexorable. Heparin is and anticoagulant often administered with fenofibric acid in cardiac treatments. A reverse phased high-performance liquid chromatography method based on photo diode array detection has been developed for their simultaneous determination from admixture. They were separated using potassium dihydrogen orthophosphate: acetonitrile (20:80, V/V), on C18 column, at a flow rate of 0.8 mL/min. The retention time of Heparin and fenofibric acid was 3.8 and 13.1 min, respectively. The validation parameters were studied as per ICH guidelines to ascertain the validity of the method for the purpose intended. The linearity was observed between 0.5-3 I.U./mL of heparin and 0.25-1.5 µg/mL of fenofibric acid. The method was applied to a synthetically prepared admixture, and found to be satisfactorily resolving two drugs without any interference, with good precision and reproducibility in the established condition.

Rosuvastatin and Fenofibrate Combination in The Treatment of Mixed Hyperlipidemia: A Narrative Review

Introduction: Patients with mixed dyslipidemia are presented with high levels of low-density lipid cholesterol (LDL-C), triglycerides (TG), and reduced high-density lipid cholesterol (HDL-C). Though useful in lowering LDL-C, therapy with rosuvastatin is insufficient in optimizing the overall lipid profile, thus putting the patient at risk of residual cardiovascular risk. A combination of statin with other lipid-modifying agents has been used with more efficient lipid control and cardiovascular risk prevention. Of these, fenofibric acid is the most frequently used, along with rosuvastatin. Methods: Authors conducted a literature search of published literature to assess the use of rosuvastatin and fenofibrate combination in the management of mixed hyperlipidaemia. Results and discussion: The authors selected a total of 46 articles to be included in the review. Due to the small number of articles and heterogeneity on the combination of rosuvastatin and fenofibrate combination in mixed hyperlipidemia, the findings herein are presented using narrative summaries. Based on the thorough assessment of the selected literature, the essential themes that emerged from the review include safety and efficacy of rosuvastatin and fenofibrate combination, place of therapy of rosuvastatin, and fenofibrate combination, and potential cardiovascular risk reduction with rosuvastatin and fenofibrate combination. Conclusion: Based on the review, the authors suggested that the combination therapy with fenofibric acid was beneficial, well-tolerated with a similar safety profile compared with statin monotherapy. The combination therapy of moderate dose rosuvastatin and fenofibric acid led to a reduction of cardiovascular risk factors via several pathways.

The hyperlipidaemic drug fenofibrate significantly reduces infection by SARS-CoV-2 in cell culture models

The SARS-CoV-2 pandemic has caused a significant number of fatalities and worldwide disruption. To identify drugs to repurpose to treat SARS-CoV-2 infections, we established a screen to measure dimerization of ACE2, the primary receptor for the virus. This screen identified fenofibric acid, the active metabolite of fenofibrate. Fenofibric acid also destabilized the receptor binding domain (RBD) of the viral spike protein and inhibited RBD binding to ACE2 in ELISA and whole cell binding assays. Fenofibrate and fenofibric acid were tested by two independent laboratories measuring infection of cultured Vero cells using two different SARS-CoV-2 isolates. In both settings at drug concentrations which are clinically achievable, fenofibrate and fenofibric acid reduced viral infection by up to 70%. Together with its extensive history of clinical use and its relatively good safety profile, these studies identify fenofibrate as a potential therapeutic agent requiring urgent clinical evaluation to treat SARS-CoV-2 infection.TeaserThe approved drug fenofibrate inhibits infection by SARS-COV-2