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/

In vitro permeability and in vivo pharmacokinetics of pemafibrate were investigated in human intestinal and animal models untreated or pretreated with cyclosporine A or rifampicin to evaluate any drug interactions. Ratios of basal to apical apparent permeability (Papp) over apical to basal Papp in the presence of pH gradients decreased from 0.37 to 0.080 on rifampicin co-incubation, suggesting active transport of pemafibrate from basal to apical sides in intestinal models. Plasma concentrations of intravenously administered pemafibrate were enhanced moderately in control mice but only marginally in humanized-liver mice by oral pretreatment with rifampicin [an organic anion transporting polypeptide (OATP) 1B1 inhibitor] 1 h before the administration of pemafibrate. In three cynomolgus monkeys genotyped as wild-type OATP1B1 (2 homozygous and 1 heterozygous), oral dosing of cyclosporine A 4 h or rifampicin 1 h before pemafibrate administration significantly increased the areas under the plasma concentration-time curves (AUC) of intravenously administered pemafibrate by 4.9- and 7.4-fold, respectively. Plasma AUC values of three pemafibrate metabolites in cynomolgus monkeys were also increased by cyclosporine A or rifampicin. These results suggested that pemafibrate was actively uptaken in livers and rapidly cleared from plasma in cynomolgus monkeys; this rapid clearance was suppressible by OATP1B1 inhibitors.Drug Metab Pharmacokinet. 2020 Aug;35(4):354-360.

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Elevated triglyceride levels are associated with an increased risk of cardiovascular events despite guideline-based statin treatment of low-density lipoprotein cholesterol. Peroxisome proliferator-activated receptor α (PPARα) agonists exert a significant triglyceride-lowering effect. However, combination therapy of PPARα agonists with statins poses an increased risk of rhabdomyolysis, which is rare but a major concern of the combination therapy. Pharmacokinetic interaction is suspected to be a contributing factor to the risk. To examine the potential for combination therapy with the selective PPARα modulator (SPPARMα) pemafibrate and statins, drug-drug interaction studies were conducted with open-label, randomized, 6-sequence, 3-period crossover designs for the combination of pemafibrate 0.2 mg twice daily and each of 6 statins once daily: 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), involving healthy male volunteers. The pharmacokinetic parameters of pemafibrate and each of the statins were similar regardless of coadministration. There was neither an effect on the systemic exposure of pemafibrate nor a clinically important increase in the systemic exposure of any of the statins on the coadministration although the systemic exposure of simvastatin was reduced by about 15% and its open acid form by about 60%. The HMG-CoA reductase inhibitory activity in plasma samples from the simvastatin and pemafibrate combination group was about 70% of that in the simvastatin alone group. In conclusion, pemafibrate did not increase the systemic exposure of statins, and vice versa, in healthy male volunteers. Clin Transl Sci. 2024 Aug;17(8):e13900.

Aims: Per the package insert, pemafibrate was contraindicated for use in patients with severe renal impairment despite its biliary excretion. To validate this, we evaluated the pharmacokinetics and safety of pemafibrate for 12 weeks 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 pemafibrate 0.2 mg/day or placebo within Groups A (estimated glomerular filtration rate [eGFR] ＜30 mL/min/1.73m2 without hemodialysis; pemafibrate n=4; placebo, n=2), B (hemodialysis; pemafibrate, n=4; placebo, n=1), and C (eGFR ≥ 30 and ＜60 mL/min/1.73m2 without hemodialysis; pemafibrate, n=8; placebo, n=2) for 12 weeks. Area under the concentration vs time curve within the dosing interval (τ) (AUCτ) of pemafibrate was measured after 12-week administration.
Results: The AUCτ (geometric mean) of pemafibrate was 7.333 and 7.991 ng·h/mL in Groups A+B and C, respectively; in Groups A+B to C at 12 weeks, the geometric mean ratio of pemafibrate AUCτ was 0.92 (90% confidence interval [CI]: 0.62, 1.36). The upper limit of the 90% CI was ≤ 2.0 (predetermined criterion). There was no consistent trend in the AUCτ and maximum plasma concentration of pemafibrate with/without statin use. Renal impairment degree did not affect the incidence of adverse events. No safety concerns were observed.
Conclusion: Pemafibrate repeated administration in patients with severe renal impairment did not increase pemafibrate exposure.J Atheroscler Thromb. 2024 Sep 5. doi: 10.5551/jat.64887. O

[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 is a member of the class of 1,3-benzoxazoles that is 1,3-benzoxazol-2-amine in which the amino hydrogens are replaced by 3-[(1R)-1-carboxypropoxy]benzyl and 3-(4-methoxyphenoxy)propyl groups. It is a selective peroxisome proliferator-activated receptor (PPAR)-alpha agonist that is used for the treatment of hyperlipidaemia. It has a role as a PPARalpha agonist, an antilipemic drug and a hepatoprotective agent. It is a member of 1,3-benzoxazoles, a member of methoxybenzenes, a monocarboxylic acid, an aromatic amine and a tertiary amino compound.
Pemafibrate is under investigation in clinical trial NCT03350165 (A Study of Pemafibrate in Patients With Nonalcoholic Fatty Liver Disease (NAFLD)).

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Drug Indication
Prevention of cardiovascular events in patients with elevated triglycerides levels, Treatment of hypertriglyceridaemia.

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The efficacy of peroxisome proliferator-activated receptor α-agonists (e.g., fibrates) against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) in humans is not known. Pemafibrate is a novel selective peroxisome proliferator-activated receptor α modulator that can maximize the beneficial effects and minimize the adverse effects of fibrates used currently. In a phase-2 study, pemafibrate was shown to improve liver dysfunction in patients with dyslipidaemia. In the present study, we first investigated the effect of pemafibrate on rodent models of NASH. Pemafibrate efficacy was assessed in a diet-induced rodent model of NASH compared with fenofibrate. Pemafibrate and fenofibrate improved obesity, dyslipidaemia, liver dysfunction, and the pathological condition of NASH. Pemafibrate improved insulin resistance and increased energy expenditure significantly. To investigate the effects of pemafibrate, we analysed the gene expressions and protein levels involved in lipid metabolism. We also analysed uncoupling protein 3 (UCP3) expression. Pemafibrate stimulated lipid turnover and upregulated UCP3 expression in the liver. Levels of acyl-CoA oxidase 1 and UCP3 protein were increased by pemafibrate significantly. Pemafibrate can improve the pathogenesis of NASH by modulation of lipid turnover and energy metabolism in the liver. Pemafibrate is a promising therapeutic agent for NAFLD/NASH.[2]

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Aims: Fasting and postprandial hypertriglyceridemia (PHTG) are caused by the accumulation of triglyceride (TG)-rich lipoproteins and their remnants, which have atherogenic effects. Fibrates can improve fasting and PHTG; however, reduction of remnants is clinically needed to improve health outcomes. In the current study, we investigated the effects of a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), K-877 (Pemafibrate), on PHTG and remnant metabolism. Methods: Male C57BL/6J mice were fed a high-fat diet (HFD) only, or an HFD containing 0.0005% K-877 or 0.05% fenofibrate, from 8 to 12 weeks of age. After 4 weeks of feeding, we measured plasma levels of TG, free fatty acids (FFA), total cholesterol (TC), HDL-C, and apolipoprotein (apo) B-48/B-100 during fasting and after oral fat loading (OFL). Plasma lipoprotein profiles after OFL, which were assessed by high performance liquid chromatography (HPLC), and fasting lipoprotein lipase (LPL) activity were compared among the groups. Results: Both K-877 and fenofibrate suppressed body weight gain and fasting and postprandial TG levels and enhanced LPL activity in mice fed an HFD. As determined by HPLC, K-877 and fenofibrate significantly decreased the abundance of TG-rich lipoproteins, including remnants, in postprandial plasma. Both K-877 and fenofibrate decreased intestinal mRNA expression of ApoB and Npc1l1; however, hepatic expression of Srebp1c and Mttp was increased by fenofibrate but not by K-877.Hepatic mRNA expression of apoC-3 was decreased by K-877 but not by fenofibrate. Conclusion: K-877 may attenuate PHTG by suppressing the postprandial increase of chylomicrons and the accumulation of chylomicron remnants more effectively than fenofibrate.[3]

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Diabetes mellitus accelerates the hyperglycemia susceptibility-induced injury to cardiac cells. The activation of peroxisome proliferator-activated receptor α (PPARα) decreases ischemia-reperfusion (IR) injury in animals without diabetes. Therefore, the present study hypothesized that pemafibrate may exert a protective effect on the myocardium in vivo and in vitro. A type 1 diabetes mellitus (T1DM) rat model and H9c2 cells exposed to high glucose under hypoxia and reoxygenation treatments were used in the present study. The rat model and the cells were subsequently treated with pemafibrate. In the T1DM rat model, pemafibrate enhanced the expression of PPARα in the diabetic-myocardial ischemia-reperfusion injury (D-IRI) group compared with the D-IRI group. The infarct size in the D-IRI group was reduced following pemafibrate treatment relative to the untreated group. The disruption of the mitochondrial structure and myofibrils in the D-IRI group was partially recovered by pemafibrate. In addition, to evaluate the mechanism of action of pemafibrate in the treatment of diabetic myocardial IR injury, an in vitro model was established. PPARα protein expression levels were reduced in the high glucose and hypoxia/reoxygenation (H/R) groups compared with that in the control or high glucose-treated groups. Pemafibrate treatment significantly enhanced the ATP and superoxide dismutase levels, and reduced the mitochondrial reactive oxygen species and malondialdehyde levels compared with the high glucose combined with H/R group. Furthermore, pemafibrate inhibited the expression of cytochrome c and cleaved-caspase-3, indicating its involvement in the regulation of mitochondrial apoptosis. Pemafibrate also reduced the expression of nuclear factor-κB (NF-κB), the activation of which reversed the protective effects of pemafibrate on diabetic myocardial IR injury in vitro. Taken together, these results suggested that pemafibrate may activate PPARα to protect the T1DM rat myocardium against IR injury through inhibition of NF-κB signaling.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.)