Pemafibrate is a potent PPARα agonist, with EC50s of 1 nM, 1.10 μM and 1.58 μM for h-PPARα, h-PPARγ and h-PPARδ, respectively. Pemafibrate is more than 1000 fold selective towards PPARα than PPARγ and PPARδ[1].

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Pemafibrate inhibits mitochondrial dysfunction by increasing PPARα expression.Pemafibrate suppresses mitochondria-induced apoptosis. Pemafibrate prevents mitochondrial dysfunction via the NF-κB signaling pathway.https://pmc.ncbi.nlm.nih.gov/articles/PMC7903427/

Pemafibrate (3 mg/kg, p.o.) increases plasma h-apoA-I in human apoA-I (h-apoA-I) transgenic mice, and shows higher levels of plasma h-apoA-I than fenofibrate at 300 mg/kg[1]. Pemafibrate (0.03 mg/kg) decreases levels of triglycerides and aspartate aminotransferase (AST) in PEMA-L (db/db) mice. Pemafibrate (0.1 mg/kg) not only shows such effects but increases liver weight in PEMA-H (db/db) mice. Pemafibrate enhances the pathogenesis in a rodent model of nonalcoholic steatohepatitis (NASH). Pemafibrate significantlly reduces the grade of hepatocyte ballooning in PEMA-H mice. Furthermore, Pemafibrate modulates lipid turnover and induces uncoupling protein 3 (UCP 3) expression in the liver[2]. Pemafibrate (K-877, 0.0005%) contained in high-fat diet (HFD) inhibits the body weight gain in mice. Pemafibrate significantly decreases the abundance of triglyceride (TG)-rich lipoproteins, including remnants, in postprandial plasma of mice. Pemafibrate also decreases intestinal mRNA expression of ApoB and Npc1l1[3].

The embryonic rat cardiomyocyte-derived cell line H9c2 was cultured in high-glucose DMEM supplemented with 10% FBS, 100 U/ml penicillin and 100 µg/ml streptomycin at 37˚C in a humidified incubator with 5% CO2. The cells (1x106 cells/well) were seeded into 6-well plates. Prior to the experiments, the cells were starved in 1% FBS-supplemented low glucose DMEM for 24 h and divided into the following groups: i) Low glucose (control; final concentration, 5.5 mmol/l); ii) high glucose (HG; final concentration, 33 mmol/l); iii) HG + hypoxia/reoxygenation (HG + H/R); and iv) HG + H/R + 50 nmol/l Pemafibrate. Briefly, when the cells reached 60% confluence, they were pre-treated with control or HG media for 48 h. Subsequently, the H/R model was induced by culturing the cells for 6 h in hypoxic conditions (95% N2 and 5% CO2) with 1% FBS-DMEM, followed by 4 h of reoxygenation in normal culture conditions. Pemafibrate was dissolved in DMSO (203.85 mmol/l) before being added to media.https://pmc.ncbi.nlm.nih.gov/articles/PMC7903427/

This study investigated the in vitro permeability and in vivo pharmacokinetics of pemafibrate in untreated or pretreated human intestine and animal models to assess its drug interactions. In the presence of a pH gradient, the ratio of basal-to-apical apparent permeability (Papp) to apical-to-basal apparent permeability (Papp) decreased from 0.37 to 0.080 after co-incubation with rifampin, indicating active transport of pemafibrate from the basal to the apical side in the intestinal models. In control mice, intravenous injection of pemafibrate resulted in a slight increase in plasma concentration; however, in humanized liver mice, pretreatment with rifampin (an inhibitor of organic anion transport peptide (OATP) 1B1) for 1 hour resulted in only a slight increase in plasma concentration. In three wild-type OATP1B1 cynomolgus monkeys (two homozygous and one heterozygous), oral administration of cyclosporine A 4 hours before intravenous pemafibrate or rifampin 1 hour before intravenous pemafibrate significantly increased the area under the plasma concentration-time curve (AUC) of intravenous pemafibrate by 4.9 and 7.4 times, respectively. Cyclosporine A or rifampin also increased the plasma AUC of three pemafibrate metabolites in the cynomolgus monkeys. These results indicate that pemafibrate is actively taken up by the liver and rapidly cleared from the plasma in cynomolgus monkeys; this rapid clearance can be inhibited by OATP1B1 inhibitors. Drug Metab Pharmacokinet. 2020 Aug;35(4):354-360.

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Even with statin treatment for low-density lipoprotein cholesterol according to guidelines, high triglyceride levels are still associated with an increased risk of cardiovascular events. Peroxisome proliferator-activated receptor α (PPARα) agonists have a significant triglyceride-lowering effect. However, combination therapy with PPARα agonists and statins increases the risk of rhabdomyolysis, which, although rare, is one of the major risks associated with combination therapy. Pharmacokinetic interactions are considered to be one of the contributing factors to this risk. To investigate the potential of the selective PPARα modulator (SPPARMα) pemafibrate in combination with statins, we conducted an open-label, randomized, 6-sequence, 3-period crossover study in healthy male volunteers. The study protocol included pemafibrate 0.2 mg twice daily in combination with six statins (pitavastatin 4 mg/day (n = 18), atorvastatin 20 mg/day (n = 18), rosuvastatin 20 mg/day (n = 29), pravastatin 20 mg/day (n = 18), simvastatin 20 mg/day (n = 20), and fluvastatin 60 mg/day (n = 19)). Results showed that the pharmacokinetic parameters of pemafibrate were similar with each statin and were not affected by combination therapy. Although systemic exposure to simvastatin was reduced by approximately 15%, and systemic exposure to its open acid form was reduced by approximately 60%, combination therapy with statins did not affect systemic exposure to pemafibrate, nor did it lead to a clinically significant increase in systemic exposure to any of the statins. The HMG-CoA reductase inhibitory activity in plasma samples from the simvastatin and pemafibrate combination therapy group was approximately 70% of that in the simvastatin monotherapy group. In conclusion, pemafibrate does not increase systemic exposure to statins in healthy male volunteers, nor does it increase systemic exposure to statins. (Clin Transl Sci. 2024 Aug;17(8):e13900)

Objective: According to the drug's package insert, although pemafibrate is excreted in bile, it is contraindicated in patients with severe renal impairment. To validate this, we conducted a 12-week pharmacokinetic and safety assessment of pemafibrate in patients with hypertriglyceridemia and renal impairment. Methods: In this phase 4, multicenter, placebo-controlled, double-blind, parallel-group, comparative study, 21 patients were randomly assigned to group A (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2, not receiving hemodialysis; pemafibrate group n=4; placebo group n=2), group B (receiving hemodialysis; pemafibrate group n=4; placebo group n=1), and group C (eGFR ≥30 and <60 mL/min/1.73 m2, not receiving hemodialysis; pemafibrate group n=8; placebo group n=2), receiving either 0.2 mg of pemafibrate daily or placebo for 12 weeks. After 12 weeks of administration, the area under the concentration-time curve (AUCτ) of pemafibrate within the dosing interval (τ) was measured. Results: The geometric mean AUCτ of pemafibrate in groups A+B and C were 7.333 and 7.991 ng·h/mL, respectively; at 12 weeks, the geometric mean ratio of the AUCτ of pemafibrate in groups A+B to that in group C was 0.92 (90% confidence interval [CI]: 0.62, 1.36). The upper limit of the 90% CI was ≤2.0 (pre-specified standard). There was no significant correlation between the AUCτ and maximum plasma concentration of pemafibrate and the use of statins. The degree of renal impairment did not affect the incidence of adverse events. No safety issues were observed. Conclusion: Repeat administration of pemafibrate in patients with severe renal impairment does not increase pemafibrate exposure. J Atheroscler Thromb. Sep 5, 2024. doi: 10.5551/jat.64887. oxygen

[1]. Design and synthesis of highly potent and selective human\nperoxisome proliferator-activated receptor alpha agonists. Bioorg Med\nChem Lett. 2007 Aug 15;17(16):4689-93.

[2]. Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis. Sci Rep. 2017 Feb 14:7:42477.

[3]. A Novel Selective PPAR\u03b1 Modulator (SPPARM\u03b1), K-877\n(Pemafibrate), Attenuates Postprandial Hypertriglyceridemia in Mice. J\nAtheroscler Thromb. 2018 Feb 1;25(2):142-152.

Pemafibrate belongs to the 1,3-benzoxazole class of compounds, with the structure 1,3-benzoxazole-2-amine, wherein the amino hydrogen is replaced by 3-[(1R)-1-carboxypropoxy]benzyl and 3-(4-methoxyphenoxy)propyl. It is a selective peroxisome proliferator-activated receptor (PPAR)-α agonist used to treat hyperlipidemia. It has dual effects as a PPARα agonist, lipid-lowering agent, and hepatoprotective agent. It belongs to the 1,3-benzoxazole class, methoxybenzene class, monocarboxylic acid class, aromatic amine class, and tertiary amine class of compounds. Pemafibrate is currently being investigated in the clinical trial NCT03350165 (Study of Pemafibrate for the Treatment of Patients with Nonalcoholic Fatty Liver Disease (NAFLD)). Drug Indications: Prevention of cardiovascular events in patients with hypertriglyceridemia, and treatment of hypertriglyceridemia. The efficacy of peroxisome proliferator-activated receptor alpha agonists (e.g., fibrates) in human non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) remains unclear. Pemafibrate is a novel, selective peroxisome proliferator-activated receptor alpha modulator that maximizes the beneficial effects of currently used fibrates while minimizing their adverse effects. In a phase II study, pemafibrate was shown to improve liver function in patients with dyslipidemia. In this study, we first investigated the effects of pemafibrate on a rodent model of NASH. We compared the efficacy of pemafibrate and fenofibrate in a diet-induced NASH rodent model. Results showed that both pemafibrate and fenofibrate improved obesity, dyslipidemia, liver function, and the pathological state of NASH. Pemafibrate significantly improved insulin resistance and increased energy expenditure. To further investigate the mechanism of action of pemafibrate, we analyzed the expression and protein levels of genes involved in lipid metabolism and analyzed the expression of uncoupling protein 3 (UCP3). The results showed that pemafibrate could stimulate hepatic lipid turnover and upregulate the expression of UCP3. In addition, pemafibrate also significantly increased the levels of acyl-CoA oxidase 1 and UCP3 proteins. Pemafibrate can improve the pathogenesis of NASH by regulating hepatic lipid turnover and energy metabolism. Pemafibrate is a promising drug for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). [2] Objective: Fasting and postprandial hypertriglyceridemia (PHTG) is caused by the accumulation of triglyceride (TG)-rich lipoproteins and their remnants, which have atherogenic effects. Fibrates can improve fasting and PHTG; however, there is a clinical need to reduce remnants to improve health outcomes. In this study, we investigated the effects of a novel selective peroxisome proliferator-activated receptor α (SPPARMα) regulator, K-877 (pemafibrate), on PHTG and residual granule metabolism. Methods: Male C57BL/6J mice, aged 8 to 12 weeks, were fed a high-fat diet (HFD), a high-fat diet containing 0.0005% K-877, or a high-fat diet containing 0.05% fenofibrate, respectively. After 4 weeks of feeding, we measured the levels of triglycerides (TG), free fatty acids (FFA), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein (apo) B-48/B-100 in plasma after fasting and oral fat loading (OFL). High-performance liquid chromatography (HPLC) was used to assess plasma lipoprotein profiles after OFL, and the activity of fasting lipoprotein lipase (LPL) was compared among the groups. Results: Both K-877 and fenofibrate inhibited weight gain, reduced fasting and postprandial TG levels, and enhanced LPL activity in mice fed a high-fat diet (HFD). HPLC analysis showed that K-877 and fenofibrate significantly reduced the abundance of TG-rich lipoproteins (including residual lipoproteins) in postprandial plasma. Both K-877 and fenofibrate reduced the mRNA expression of ApoB and Npc1l1 in the intestine. However, fenofibrate increased the expression of Srebp1c and Mttp in the liver, while K-877 did not. K-877 reduced the mRNA expression of apoC-3 in the liver, while fenofibrate did not. Conclusion: K-877 may alleviate postprandial hyperglycemia (PHTG) more effectively than fenofibrate by inhibiting the increase of postprandial chylomicrons and the accumulation of chylomicron residues. [3] Diabetes accelerates myocardial cell damage caused by hyperglycemia susceptibility. Activation of peroxisome proliferator-activated receptor α (PPARα) can alleviate ischemia-reperfusion (IR) injury in non-diabetic animals. Therefore, this study hypothesized that pemafibrate may exert a protective effect on the myocardium in vivo and in vitro. This study used a type 1 diabetes mellitus (T1DM) rat model and H9c2 cells exposed to high glucose, hypoxia, and reoxygenation. Subsequently, the rat model and cells were treated with pemafibrate. In the T1DM rat model, pemafibrate enhanced PPARα expression in the diabetic myocardial ischemia-reperfusion injury (D-IRI) group compared to the untreated group. The infarct area was reduced in the D-IRI group after pemafibrate treatment compared to the untreated group. Pemafibrate partially restored the mitochondrial structure and myofibril damage in the D-IRI group. Furthermore, to evaluate the mechanism of action of pemafibrate in treating diabetic myocardial ischemia-reperfusion injury, an in vitro model was established. Compared with the control group or the high glucose treatment group, the expression level of PPARα protein was decreased in the high glucose combined with hypoxia/reoxygenation (H/R) group. Compared with the high glucose combined with H/R group, pemafibrate treatment significantly increased ATP and superoxide dismutase levels and decreased mitochondrial reactive oxygen species and malondialdehyde levels. Furthermore, pemafibrate inhibited the expression of cytochrome c and cleaved caspase-3, indicating their involvement in the regulation of mitochondrial apoptosis. Pemafibrate also reduced nuclear factor-κB (NF-κB) expression, and NF-κB activation reversed the in vitro protective effect of pemafibrate against myocardial ischemia-reperfusion injury in diabetic rats. In summary, these results suggest that pemafibrate may protect the myocardium of type 1 diabetic rats from ischemia-reperfusion injury by inhibiting PPARα activation through the NF-κB signaling pathway. https://pmc.ncbi.nlm.nih.gov/articles/PMC7903427/

C28H30N2O6

490.556

490.21

C, 68.56; H, 6.16; N, 5.71; O, 19.57

848259-27-8

950644-31-2 (sodium); 848258-31-1 (racemate); 848259-27-8 (free acid);

11526038

White to yellow solid powder

5.554

1

8

13

36

658

1

CC[C@H](C(=O)O)OC1=CC=CC(=C1)CN(CCCOC2=CC=C(C=C2)OC)C3=NC4=CC=CC=C4O3

ZHKNLJLMDFQVHJ-RUZDIDTESA-N

InChI=1S/C28H30N2O6/c1-3-25(27(31)32)35-23-9-6-8-20(18-23)19-30(28-29-24-10-4-5-11-26(24)36-28)16-7-17-34-22-14-12-21(33-2)13-15-22/h4-6,8-15,18,25H,3,7,16-17,19H2,1-2H3,(H,31,32)/t25-/m1/s1

(R)-2-(3-((benzo[d]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxy)butanoic acid

K877; (R)-K13675; K-877; (R)-K 13675; K 877; 848259-27-8; Pemafibrate [INN]; (R)-K-13675; K-13675, (R)-; (R)-2-(3-((benzo[d]oxazol-2-yl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxy)butanoic acid; CHEMBL247951; CAS#848259-27-8; (R) K-13675; Pemafibrate sodium; (R)-K 13675; Parmodia

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)