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Central Luzon Doctors Hospital Educational Institution San Pablo, Tarlac City

Submitted by:

Ann Charmaine D. Basilio


BSN III-B Submmitted to

Joahne Tipay RN, MSN


Clinical Instructor

Bardoxolone Methyl

(also known as RTA 402 and CDDO-methyl ester)

The drug, known as bardoxolone methyl, works in a new way, says researcher David Warnock, MD, the Hilda B. Anderson professor of medicine at the University of Alabama at Birmingham. He is slated to present the results of the phase II trial of the drug today at the European Renal Association-European Dialysis and Transplant Association Congress in Prague. Classification Anti-Inflammatory Indication Oral Mechanism of Action Bardoxolone methyl, an antioxidant inflammation modulator, activates the Keap1Nrf2 pathway, which plays an important role in maintaining kidney function and structure. The chemical and biologic characteristics of bardoxolone methyl, a derivative of the natural product oleanolic acid, have been reviewed recently. Bardoxolone methyl interacts with cysteine residues on Keap1, allowing Nrf2 translocation to the nucleus and subsequent up-regulation of a multitude of cytoprotective genes. The structure and activity profile of bardoxolone methyl resemble those of the cyclopentenone prostaglandins, endogenous Nrf2 activators that promote the resolution of inflammation. Like cyclopentenone prostaglandins, bardoxolone methyl exerts antiinflammatory effects by inhibiting the proinflammatory nuclear factor B pathway.

Adverse Effects The most common adverse event among patients receiving bardoxolone methyl was muscle spasm, with an incidence of 42% in the 25-mg group, 61% in the 75-mg group, and 59% in the 150-mg group, as compared with 18% in the placebo group. Mild elevations in alanine aminotransferase levels and gastrointestinal effects. Of the 170 patients who received bardoxolone methyl, 120 (71%) had transient aminotransferase elevations that peaked within 2 to 4 weeks after the initiation of treatment or an increase in the dose and generally resolved while the patients continued to take the drug. A total of 18 patients (11%) had an alanine aminotransferase elevation of more than three times the upper limit of the normal range.

PIRFENIDONE
Pirfenidone is a drug developed by InterMune Inc. for the treatment of idiopathic pulmonary fibrosis. In 2011 it was approved for use in Europe for idiopathic pulmonary fibrosis (IPF) under the trade name Esbriet. The proposed trade name in the US is also Esbriet. In Japan it is marketed as Pirespa by Shionogi & Co. In October 2010, the Indian Company Cipla launched it as Pirfenex. Indication Pirfenidone is indicated in the treatment of idiopathic pulmonary fibrosis. Contraindication Pirfenidone is contraindicated in patients who have documented hypersensitivity to pirfenidone. It is also contraindicated in patients with severe hepatic impairment and renal impairment. Pirfenidone is contraindicated in patients who are on concomitant therapy with any of the CYP1A2 inhibitors such as fluvoxamine. Pharmacokinetics Pirfenidone is administered orally. Though the presence of food significantly reduces the extent of absorption, the drug is to be taken after food, to reduce the nausea and dizziness associated with the drug. The drug is around 60% bound to plasma proteins, especially to albumin.. Up to 50% of the drug is metabolized by hepatic CYP1A2 enzyme system to yield 5-carboxypirfenidone, the inactive metabolite. Almost 80% of the administered dose is excreted in the urine within 24 hours of intake.

Adverse Effects Gastrointestinal Pirfenidone is frequently associated with gastrointestinal side effects such as dyspepsia, nausea, diarrhea, gastroesophageal reflux disease (GERD) and vomiting. To reduce the severity of these reactions, pirfenidone is to be taken after meals. Skin Pirfenidone is known to cause photosensitivity reactions, rash, pruritus and dry skin. The photosensitivity reactions can be troublesome; there is also the risk of carcinogenic transformation of skin after direct exposure to sunlight. Patients are usually advised to avoid direct exposure to sunlight, including sun lamps, by using protective clothing and sunscreen agents. When developed, photosensitivity reactions are usually managed by dose adjustment and temporary discontinuation of treatment if required, along with local symptomatic treatment. Hepatic dysfunction Pirfenidone is known to increase hepatic enzyme levels, esecially those of aspartate transaminase (AST), alanine transaminase (ALT) and gamma-glutamyl transpeptidase (GGT); periodic monitoring of hepatic enzyme levels is required during therapy: once before the initiation of therapy, monthly monitoring upto 6 months after initiation of therapy, and 3 monthly therearter. Extra precaution is required while prescribing the drug in patients with hepatic impairment and in patients who are on concomitant therapy

with CYP1A2 inhibitors. The drug is contraindicated in patients who have severe hepatic impairment. Dizziness and fatigue Dizziness and fatigue are very frequently reported adverse drug reactions with pirfenidone.The severity of these reactions may be reduced if the drug is taken after food. If severe, treatment discontinuation may be required.[5] Weight loss Pirfenidone is reported to cause weight loss in various clinical trials. Interactions Most drug interactions are mediated by various cytochrome P450 (CYP) enzymes. CYP1A2 inhibitors Since Pirfenidone is metabolised through the CYP1A2 enzyme pathway, any drug which inhibits this enzyme is likely to precipitate the toxicity of pirfenidone: concomitant therapy is to be avoided. Fluvoxamine being one such drug is in fact contraindicated in patients who are on treatment with pirfenidone. Other inhibitors of CYP1A2 such as ciprofloxacin, amiodarone and propafenone should be used with caution. Other CYP inhibitors Some amount of pirfenidone is also metabolized by CYP enzymes other than CYP1A2. Consequently, strong inhibitors of other CYP systems such as fluconazole (CYP2C9), chloramphenicol (CYP2C19), fluoxetine and paroxetine (both CYP2D6) should be used with caution. CYP1A2 inducers Moderate inducers of CYP1A2 such as omeprazole should be used with caution since they might reduce the circulating plasma levels of the drug. Cigarette smoking Cigarette smoking causes increased clearance of pirfenidone by inducing CYP1A2. Patients must be advised to abstain from cigarette smoking while on therapy with pirfenidone.

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