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.
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.
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.
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.
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.
来源:DrugBank
吸收、分配和排泄
分布容积
平均表观口服分布容积大约为59到71升。吡非尼酮在组织中分布不广泛。
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.
[EN] CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF<br/>[FR] MODULATEURS DE CALPAÏNE ET LEURS UTILISATIONS THÉRAPEUTIQUES
申请人：BLADE THERAPEUTICS INC
公开号：WO2019190885A1
公开（公告）日：2019-10-03
Small molecule calpain modulator compounds, including their pharmaceutically acceptable salts, can be included in pharmaceutical compositions. The compounds can be useful in inhibiting calpain, or competitive binding with calpastatin, by contacting them with CAPN1, CAPN2, and/or CAPN9 enzymes residing inside a subject. The compounds and composition can also be administered to a subject in order to treat a fibrotic disease or a secondary disease state or condition of a fibrotic disease.
The embodiments provide compounds of the general Formulae I, II, III, IV, or V as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.
NOVEL DIHYDROPYRIMIDINOISOQUINOLINONES AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS.
申请人：GALAPAGOS NV
公开号：US20130165437A1
公开（公告）日：2013-06-27
A compound according to Formula Ia:
wherein L
1
, G, and R
1
are as described herein.
The present invention relates to novel compounds according to Formula I that antagonize GPR84, a G-protein-coupled receptor that is involved in inflammatory conditions, and methods for the production of these novel compounds, pharmaceutical compositions comprising these compounds, and methods for the prevention and/or treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions by administering a compound of the invention.
[EN] ANTICANCER BENZOPYRAZINES VIA THE INHIBITION OF FGFR KINASES<br/>[FR] BENZOPYRAZINES ANTICANCÉREUSES PAR LE BIAIS DE L'INHIBITION DE FGFR KINASES
申请人：ASTEX THERAPEUTICS LTD
公开号：WO2013061081A1
公开（公告）日：2013-05-02
The invention relates to new quinoxaline derivative compounds, to pharmaceutical compositions comprising said compounds, to processes for the preparation of said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.
Macrocyclic compounds as inhibitors of viral replication
申请人：Blatt M. Lawrence
公开号：US20050267018A1
公开（公告）日：2005-12-01
The embodiments provide compounds of the general formulas I-XIX, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating flaviviral infection, including hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.
