The furin substrate matrix metalloproteinase (MMP)-11, a TGF-β target gene implicated in carcinogenesis, had its protein levels decreased by pirfenidone (PFD). According to these findings, PFD or PFD-related medicines are prospective treatments for human malignancies linked to increased TGF-β activity[1]. Through a translational mechanism, pirfenidone inhibits the proinflammatory cytokine TNF-α in RAW264.7 cells, a murine macrophage-like cell line, without requiring activation of MAPK2, p38 MAPK, or JNK. Pirfenidone significantly reduces the synthesis of proinflammatory cytokines such as TNF-α, interferon-γ, and interleukin-6 in the murine endotoxin shock model, while increasing the synthesis of interleukin-10, an anti-inflammatory cytokine[2]. PFD (pirfenidone) exhibits its inhibitory effects on HLEC growth. After 24 hours, there is a reduction in cell growth in the 0.3 mg/mL group compared to the control group (P=0.044). At 24, 48, and 72 hours, the impact is more noticeable in the 0.5 mg/mL group (P<0.05). At all time points, 1 mg/mL PFD virtually entirely inhibits growth (P<0.01)[3].

Pirfenidone (300 mg/kg/day) was administered for four weeks. When pirfenidone is given to mice treated with Bleomycin (BLM), the score is dramatically reduced (P<0.0001). In addition, lung collagen content is measured in order to assess Pirfenidone's anti-fibrotic properties. When compared to mice treated with saline or pirfenidone, the lungs of BLM-treated mice have a significantly higher collagen content, and this rise is dramatically reduced when pirfenidone is administered on day 28 following BLM treatment (P=0.0012)[4].

Absorption, Distribution and Excretion
After a single oral-dose administration of 801 mg pirfenidone (as three 267 mg capsules), the Tmax ranged from 30 minutes to four hours. Food affects the absorption and safety profile of pirfenidone: in one study, food increased Tmax; decreased Cmax and AUC by 49% and 16%, respectively; and decreased the incidence of pirfenidone-induced adverse reactions.
Within 24 hours, approximately 80% of the pirfenidone dose is excreted mainly in the urine. About 99.6% of the recovered dose of pirfenidone was excreted as the 5-carboxy metabolite. About less than 1% of the dose was excreted as unchanged parent drug and less than 0.1% of the dose was excreted as other metabolites.
Mean apparent oral volume of distribution is approximately 59 to 71 L. Pirfenidone is not widely distributed to tissues.
Following administration of a single dose of 801 mg in healthy older adults, the mean apparent oral clearance of pirfenidone was 13.8 L/h with food and 11.8 L/h without food.
Esbriet binds to human plasma proteins, primarily to serum albumin, in a concentration-independent manner over the range of concentrations observed in clinical trials. The overall mean binding was 58% at concentrations observed in clinical studies (1 to 10 ug/mL). Mean apparent oral volume of distribution is approximately 59 to 71 liters.
After single oral-dose administration of 801 mg Esbriet, the maximum observed plasma concentration (Cmax) was achieved between 30 minutes and 4 hours (median time of 0.5 hours). Food decreased the rate and extent of absorption. Median Tmax increased from 0.5 hours to 3 hours with food. Maximum plasma concentrations and AUC0-inf decreased by approximately 49% and 16% with food, respectively.
Pirfenidone is excreted predominantly as metabolite 5-carboxy-pirfenidone, mainly in the urine (approximately 80% of the dose). The majority of Esbriet was excreted as the 5-carboxy metabolite (approximately 99.6% of that recovered).
/MILK/ A study with radio-labeled pirfenidone in rats has shown that pirfenidone or its metabolites are excreted in milk. It is not known whether Esbriet is excreted in human milk.
... This study aimed to evaluate the pharmacokinetics and urinary excretion of pirfenidone and its major metabolite 5-carboxy-pirfenidone in healthy Chinese subjects under fed conditions. 20 healthy subjects of either sex were recruited in this randomized, single-center, and open-label, single ascending doses (200, 400, and 600 mg) and multiple doses (400 mg, 3 times daily) study. Safety was assessed by adverse events, ECGs, vital signs, and clinical laboratory parameters. Blood and urine samples were analyzed with a validated LC/MS method. Pirfenidone was safe and well tolerated. After single-dose administration, pirfenidone was rapidly absorbed with a mean Tmax of 1.8-2.2 hr and a mean half life of 2.1-2.4 hr. 5-carboxy-pirfenidone was rapidly formed with a mean Tmax of 1.5-2.2 hr and a mean half life of 2.1-2.6 hr. Cmax and AUC for both parent and metabolite were dose proportional over the 200-600 mg dose range. No gender effect was found. In the steady state, the accumulation index (R) estimated for the 3 dosing intervals ranged from 1.1 to 1.5 for both pirfenidone and 5-carboxy-pirfenidone, indicating that the exposure of pirfenidone and 5-carboxy-pirfenidone increased slightly with repeated dosing, but half life and CL/F remained unchanged. Metabolism is the primary mechanism of drug clearance of pirfenidone. About 87.76% of the administered pirfenidone was excreted in urine in the form of 5-carboxy-pirfenidone, while only 0.6159% of the administered pirfenidone was detected as the unchanged form in urine.

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Metabolism / Metabolites
According to _in vitro_ studies, about 70-80% of pirfenidone metabolism is mediated by CYP1A2, as well as some minor contributions from CYP2C9, 2C19, 2D6, and 2E1. Four metabolites have been detected after oral administration of pirfenidone. _In vitro_ data suggest that metabolites are not expected to be pharmacologically active at observed metabolite concentrations. The exact metabolic pathways of pirfenidone have not been fully characterized; however, one of the pathways involve CYP1A2-mediated 5-hydroxylation and subsequent oxidation to form 5-carboxy pirfenidone. In humans, only pirfenidone and 5-carboxy pirfenidone are present in plasma in significant quantities. The mean metabolite-to-parent ratio ranged from approximately 0.6 to 0.7.
Pirfenidone is excreted predominantly as metabolite 5-carboxy-pirfenidone, mainly in the urine (approximately 80% of the dose). The majority of Esbriet was excreted as the 5-carboxy metabolite (approximately 99.6% of that recovered).
In vitro profiling studies in hepatocytes and liver microsomes have shown that Esbriet is primarily metabolized in the liver by CYP1A2 and multiple other CYPs (CYP2C9, 2C19, 2D6, and 2E1). Oral administration of Esbriet results in the formation of four metabolites. In humans, only pirfenidone and 5-carboxy-pirfenidone are present in plasma in significant quantities. The mean metabolite-to-parent ratio ranged from approximately 0.6 to 0.7. No formal radiolabeled studies have assessed the metabolism of pirfenidone in humans. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.

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Biological Half-Life
The mean terminal half-life is approximately three hours in healthy subjects.
The mean terminal half-life is approximately 3 hours in healthy subjects.
... This study aimed to evaluate the pharmacokinetics and urinary excretion of pirfenidone and its major metabolite 5-carboxy-pirfenidone in healthy Chinese subjects under fed conditions. 20 healthy subjects of either sex were recruited in this randomized, single-center, and open-label, single ascending doses (200, 400, and 600 mg) and multiple doses (400 mg, 3 times daily) study. ... After single-dose administration, pirfenidone was rapidly absorbed with a mean ... half life of 2.1-2.4 hr. 5-carboxy-pirfenidone was rapidly formed with ... a mean half life of 2.1-2.6 hr. ...

Toxicity Summary
IDENTIFICATION AND USE: Pirfenidone is a white solid. It is used as medication for the treatment of idiopathic pulmonary fibrosis. HUMAN EXPOSURE AND TOXICITY: Reports of angioedema (some serious) such as swelling of the face, lips and/or tongue which may be associated with difficulty breathing or wheezing have been reported with use of pirfenidone in the post-marketing setting. ANIMAL STUDIES: In a 24-month carcinogenicity study in rats, pirfenidone caused statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma in male rats at doses of 750 mg/kg and above (AUC exposure approximately 1.9 times adult exposure at the MRDD). There were statistically significant increases of the combination of hepatocellular adenoma and carcinoma and the combination of uterine adenocarcinoma and adenoma at a dose of 1500 mg/kg/day (AUC exposure approximately 3.0 times adult exposure at the MRDD). In a 24-month carcinogenicity study in mice, pirfenidone caused statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma and hepatoblastoma in male mice at doses of 800 mg/kg and above (AUC exposure approximately 0.4 times adult exposure at the MRDD). There were statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma in female mice at doses of 2000 mg/kg and above (AUC exposure approximately 0.7 times adult exposure at the MRDD). Pirfenidone had no effects on fertility and reproductive performance in rats at dosages up to 1000 mg/kg/day (approximately 3 times the MRDD in adults on a mg/sq m basis). A fertility and embryo-fetal development study with rats and an embryo-fetal development study with rabbits that received oral doses up to 3 and 2 times, respectively, the maximum recommended daily dose (MRDD) in adults (on mg/sq m basis at maternal doses up to 1000 and 300 mg/kg/day, respectively) revealed no evidence of impaired fertility or harm to the fetus due to pirfenidone. In the presence of maternal toxicity, acyclic/irregular cycles were seen in rats at doses approximately equal to and higher than the MRDD in adults (on a mg/sq m basis at maternal doses of 450 mg/kg/day and higher). In a pre- and post-natal development study, prolongation of the gestation period, decreased numbers of live newborn, and reduced pup viability and body weights were seen in rats at an oral dosage approximately 3 times the MRDD in adults (on a mg/sq m basis at a maternal dose of 1000 mg/kg/day). Pirfenidone was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacteria, a chromosomal aberration test in Chinese hamster lung cells, and a micronucleus test in mice. No genotoxic effects were observed neither in newborn rats transplacentally exposed to pirfenidone, or in two adult rodent models when pirfenidone was administered orally or topically.

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Hepatotoxicity
In large randomized controlled trials, serum aminotransferase elevations more than 3 times the upper limit of normal (ULN) occurred in 4% of pirfenidone- compared to less than 1% of placebo-treated patients. The elevations were generally asymptomatic and short lived, resolving with or without dose modification and requiring drug discontinuation in approximately 1% of patients. Despite the frequency of serum enzyme elevations during therapy, clinically apparent liver injury was not reported in preregistration studies. Nevertheless, since the general availability of pirfenidone in the United States and during years of clinical use elsewhere, there have been isolated case reports of clinically apparent liver injury due to pirfenidone, some of which were severe and even fatal. The latency to onset ranged from one month to one year and the injury was usually hepatocellular or mixed. Immunoallergic features were not common.
Likelihood score: D (possible rare cause of clinically apparent liver injury).

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Protein Binding
At a dose range of 1 to 10 μg/mL, pirfenidone was approximately 58% bound to human plasma proteins, mainly to serum albumin.

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Interactions
Concomitant use of pirfenidone and CYP1A2 inducers may result in decreased exposure to and reduced efficacy of pirfenidone. The manufacturer of pirfenidone recommends that potent CYP1A2 inducers be avoided during pirfenidone therapy.
Concomitant use of pirfenidone with agents or a combination of agents that are potent or moderate inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved with pirfenidone metabolism (i.e., CYP2C9, 2C19, 2D6, and 2E1) should be avoided.
Concomitant administration of a single dose of pirfenidone with the potent CYP1A2 inhibitor fluvoxamine (initially 50 mg daily, titrated upward to 150 mg daily for 10 days) in nonsmokers and smokers increased pirfenidone exposure approximately fourfold in nonsmokers and sevenfold in smokers.
Concomitant administration of pirfenidone (single 801-mg dose on day 6) with the moderate CYP1A2 inhibitor ciprofloxacin (750 mg twice daily on days 2-7) increased the systemic exposure to pirfenidone by 81%. Pirfenidone dosage should be reduced if used concomitantly with ciprofloxacin at a dosage of 750 mg twice daily. No initial dosage adjustment is recommended if pirfenidone is used concomitantly with ciprofloxacin at a dosage of 250 or 500 mg once daily; however, patients receiving such concomitant therapy should be monitored closely for adverse effects.
For more Interactions (Complete) data for Pirfenidone (8 total), please visit the HSDB record page.

[1]. Pirfenidone inhibits TGF-beta expression in malignant glioma cells. Biochem Biophys Res Commun. 2007 Mar 9;354(2):542-7.

[2]. A novel anti-fibrotic agent pirfenidone suppresses tumor necrosis factor-alpha at the translational level. Eur J Pharmacol. 2002 Jun 20;446(1-3):177-85.

[3]. Inhibition of Pirfenidone on TGF-beta2 induced proliferation, migration and epithlial-mesenchymal transitionof human lens epithelial cells line SRA01/04. PLoS One. 2013;8(2):e56837.

[4]. Pirfenidone inhibits fibrocyte accumulation in the lungs in bleomycin-induced murine pulmonary fibrosis. Respir Res. 2014 Feb 8;15:16.

[5]. Limited fibrosis accompanies triple-negative breast cancer metastasis in multiple model systems and is not a preventive target. Oncotarget. 2018 May 4;9(34):23462-23481.

Therapeutic Uses
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Pirfenidone is included in the database.
Esbriet is indicated for the treatment of idiopathic pulmonary fibrosis (IPF). /Included in US product label/
/EXPL THER/ Left ventricular remodeling is a frequent complication of hypertension with no therapeutic treatment available for the subsequent onset of myocardial fibrosis. Pirfenidone is an antifibrotic small-molecular-size drug with anti-inflammatory properties that is used as a treatment for fibrotic diseases, but its effects on hypertension-induced myocardial fibrosis are unknown. Therefore, we tested whether pirfenidone could ameliorate hypertension-induced left ventricular remodeling and whether hypertension-induced NLRP3 (Nod-like receptor pyrin domain containing 3), a critical protein in NLRP3 inflammasome formation, is involved in the therapeutic mechanism. A TAC-induced mouse model of hypertension and left ventricular hypertrophy was treated with pirfenidone, and survival, collagen deposition by histopathologic examination, heart function by echocardiography, concentrations of fibrosis-related inflammatory cytokines TGF-beta1, IL-1beta in heart homogenate and in vitro cell cultures by ELISA, levels of ROS and inflammatory cells by flow cytometry, and levels of NLRP3 by Western blotting and immunohistochemistry were measured. Pirfenidone increased the survival rate and attenuated myocardial fibrosis and inflammatory mediators in the TAC-induced hypertension-complicated left ventricular remodeling mouse model. The inhibition of NLRP3 expression by pirfenidone attenuated the expression of IL-1beta and IL-1beta-induced inflammatory and profibrotic responses. Pirfenidone may be useful in the treatment of hypertension-induced myocardial fibrosis by inhibiting NLRP3-induced inflammation and fibrosis.
/EXPL THER/ Systemic sclerosis (SSc)-associated interstitial lung disease (SSc-ILD) has become the leading SSc-related cause of death. Although various types of immunosuppressive therapy have been attempted for patients with SSc-ILD, no curative or effective treatment strategies for SSc-ILD have been developed. Therefore, management of patients with SSc-ILD remains a challenge. Here, we report a Chinese, female, SSc-ILD patient who was negative for Scl-70 and showed an excellent response to pirfenidone without obvious adverse effects. She had been suffered from dry cough and exertional dyspnea for 2 months. The chest computed tomography manifestation was consistent with a pattern of fibrotic nonspecific interstitial pneumonia. The pulmonary function test showed isolated impaired diffusion. After 11 weeks of administration of pirfenidone, the dry cough and dyspnea had disappeared. Both of the lung shadows and the pulmonary diffusion function were improved. Pirfenidone might be an effective option for early SSc-ILD treatment. A well-controlled clinical trial is expected in the future.

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Drug Warnings
Elevations in serum transaminase (ALT and/or AST) concentrations exceeding 3 times the upper limit of normal (ULN) have occurred in patients receiving pirfenidone; concomitant elevations in bilirubin concentrations have been reported rarely. ALT or AST elevations of at least 3 times the ULN were reported in 3.7% of patients receiving pirfenidone compared with 0.8% of patients receiving placebo in clinical studies; ALT or AST elevations of 10 times the ULN or greater occurred in 0.3% of pirfenidone-treated patients. Increases in liver enzymes were reversible following dosage modification or interruption of therapy. No cases of liver transplant or death due to liver failure related to pirfenidone use have been reported to date; however, the manufacturer states that the combination of transaminase elevations and hyperbilirubinemia without evidence of obstruction is generally recognized as an important predictor of severe liver injury possibly resulting in death or the need for liver transplant in some patients. Liver function tests including ALT, AST, and bilirubin concentrations should be performed prior to initiation of pirfenidone therapy, monthly for the first 6 months, and then every 3 months thereafter. Interruption of therapy and/or dosage reduction may be necessary in patients experiencing liver enzyme elevations.
Cigarette smoking reduces peak plasma concentrations and systemic exposure to pirfenidone by 32 and 54%, respectively. The manufacturer recommends that patients be encouraged to stop smoking prior to initiation of pirfenidone and to avoid smoking during therapy.
There are no adequate and well-controlled studies of Esbriet in pregnant women. Pirfenidone was not teratogenic in rats and rabbits. Because animal reproduction studies are not always predictive of human response, Esbriet should be used during pregnancy only if the benefit outweighs the risk to the patient.
Adverse effects reported in 10% or more of patients receiving pirfenidone and at an incidence greater than with placebo include nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, dyspepsia, dizziness, vomiting, anorexia, gastroesophageal reflux disease (GERD), sinusitis, insomnia, decreased weight, and arthralgia.
For more Drug Warnings (Complete) data for Pirfenidone (16 total), please visit the HSDB record page.

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Pharmacodynamics
Pirfenidone is a novel agent with anti-inflammatory, antioxidant, and antifibrotic properties. It may improve lung function and reduce the number of acute exacerbations in patients with idiopathic pulmonary fibrosis (IPF).

C12H11NO

185.22

185.084

53179-13-8

40632

White to light yellow solid powder

1.1±0.1 g/cm3

329.1±15.0 °C at 760 mmHg

96-97ºC

152.7±11.6 °C

0.0±0.7 mmHg at 25°C

1.592

1.82

0

1

1

14

285

0

ISWRGOKTTBVCFA-UHFFFAOYSA-N

InChI=1S/C12H11NO/c1-10-7-8-12(14)13(9-10)11-5-3-2-4-6-11/h2-9H,1H3

5-methyl-1-phenylpyridin-2-one

S-7701, AMR-69; S 7701, AMR69; S7701, AMR-69; AMR 69; Pirfenidone; trade name: Pirespa; Pirfenex; Deskar, Esbriet; Etuary.

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)

Solubility in Formulation 1: ≥ 2.75 mg/mL (14.85 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.75 mg/mL (14.85 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (11.23 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 4: ≥ 2.08 mg/mL (11.23 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 5: ≥ 2.08 mg/mL (11.23 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 6: 2% DMSO+30% PEG 300+ddH2O:10 mg/mL

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Solubility in Formulation 7: 9.09 mg/mL (49.08 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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Solubility in Formulation 8: 6.67 mg/mL (36.01 mM) in Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 9: 20 mg/mL (107.98 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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