Fenofibric acid

Case II Analysis of Fenofibric Acid Using Dual Online SPE for Clinical... 

Several clinical studies revealed that administration of fenofibrate produces reductions in total-C, LDL-C, apo B, total triglycerides, and triglyceride-rich (very low density) lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in HDL-C, apo AI, and apo AIL However, since fenofibrate is rapidly converted to fenofibric acid during absorption and fenofibric acid, but not fenofibrate, is found circulating in plasma, the effects of fenofibric acid have been extensively evaluated in these studies. 

The objective of study M06-830 is to evaluate the bioavailability of fenofibric acid from the fenofibric acid choline salt formulation manufactured at full production scale at Abbott Laboratories Puerto Rico facility relative to the bioavailability of (1) the fenofibric acid choline salt formulation used in Phase 3 trials and manufactured at the Abbott Park facility, and (2) the 200 mg micronized fenofibrate capsule. 

Recovery — Recovery control (RC) solutions were prepared in 10/90 v/v ACN/water. Recovery evaluation (RE) samples were prepared in human plasma. Aliquot of RC solutions into assay plates followed sample preparation procedure steps 1 and 2. Instead of adding 50 pL of diluent, wells containing RC solutions were dried down under a steady stream of room temperature N2. The dried wells were then reconstituted with 250 pL of diluent. Reconstituted RC solutions were directly injected onto an HPLC analytical column, bypassing the extraction column. RE samples were aliquoted into an assay plate following normal sample preparation. RE samples were analyzed using the full extraction procedure (with extraction column). The analyte was tested at three concentration levels and the internal standard was tested at one. Mean extraction recovery for fenofibric acid varied from 93.2 to 111.1%, and mean extraction recovery for the Pestanal internal standard was 105.2%. 

Stability — Samples remained stable for at least 220 days when frozen at -20°C. They were stable for 7 simulated ffeeze-and-thaw cycles and approximately 44 hr at room temperature. The analyte was viable at least 2 days in the autosampler (temperature set point at 10°C). The batch was stable for 5 days in a refrigerator (temperature varied from 4 to 8°C). A stock solution of fenofibric acid is stable at least 50 days the stock solution for internal standard is stable at least 10 days under refrigeration. 

Another therapeutic class to be briefly discussed is that of the lipid-lowering agents known as fibrates, e.g., clofibrate and fenofibrate (8.5). Here also, the acidic metabolite is the active form clofibrate (an ethyl ester) is rapidly hydrolyzed to clofibric acid by liver carboxylesterases and blood esterases [11], Human metabolic studies of fenofibrate (8.5), the isopropyl ester of fenofibric acid, showed incomplete absorption after oral administration, while hydrolysis of the absorbed fraction was quantitative [12], This was followed by other reactions of biotransformation, mainly glucuronidation of the carboxylic acid group. 

Absorptlon/Dlstrlbutlon - Fenofibrate is well absorbed from the Gl tract. Peak plasma levels of fenofibric acid occur within 4 to 8 hours after administration. Serum protein binding is approximately 99%. 

Metabolism - Fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid no unchanged fenofibrate is detected in plasma. Fenofibric acid is primarily conjugated with glucuronic acid. 

Excretion - Fenofibrate is eliminated with a half-life of 20 to 23 hours. It is mainly excreted in urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide approximately 60% of the dose appears in urine and 25% in feces. 

Elderly Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, take care in dose selection. 

The fibrates are another class of antihyperlipidemic drug and are frequently coadministered with a statin. Fibrates act as agonists of the peroxisome proliferator-activated receptors (PPAR), particularly PPAR-a. PPARs are nuclear receptors that influence gene expression and lipid metabolism. Examples of fibrates include gemfibrozil (Lopid, A.110) and fenofibrate (Tricor, A.lll) (Figure A.30). Fenofibrate is hydrolyzed in the body to its active form, fenofibric acid (A.112). Fibrates do not decrease LDL levels as effectively as statins, but fibrates do elevate HDL cholesterol levels. 

PPARa activator in humans—clofibric acid, fenofibric acid, pirinixic acid (WY-14643). 

Fenofibrate 30-50 (fasting) 60-90 (food) Prodrug which is rapidly and completely hydrolyzed by plasma and tissue esterases to fenofibric acid To active fenofibric acid (see activity) High (fenofibric acid)... 

The efficient photodecarboxylation of the keto acids (77) has been studied. The reactions involve the formation of the carbanions (78). Aqueous solutions of fenofibric acid (79) at pH 7.4 show the formation of two intermediates when subjected to laser excitation. The study has indicated that the triplet state of the acid in water is of a jtji type. Photoionization is an important process in the aqueous medium. New photoreactive phenylalanine analogues (80) and (81) have been prepared. These were incorporated into position 5 of the pentapeptide, thymopentin. The resultant derivatives were photolabile and underwent decomposition on irradiation at 365 nm. Computational methods have been used to analyse the photoreactivity of the tryptophan derivative (82). The calculations were directed towards an understanding of the quenching of the fluorescence. The results indicate that hydrogen transfer alone does not quench the fluorescence, but that an aborted decarboxylation path is involved. Proton transfer... 

A 7-day course of fenofibrate 67 mg three times daily and rosuvastatin 10 mg daily resulted in only minor changes in fenofibric acid and rosuvastatin exposure in 14 healthy subjects, when compared with either drug given alone. ... 

Martin PD, Dane AL, Schneck DW, Warwick MJ. An open-label, randomized, diree-way crossover ttial of the effect of coadministration of rosuvastatin and fenofibrate on die pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers. Clin Ther(2003) 25, 459-71. 

Figure 6 Analysis of fenofibric acid (F, 42 mg I h in serum by CE, with stacking. Iohexol (I) is added as internal standard. Conditions of analysis capillary of 25cm x 50pm (ID), voltage 7kV, wavelength 280nm, sample size 13% of the capillary volume. Separation buffer as in Figure 2.

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