Idiopathic Pulmonary Fibrosis (IPF)


Esbriet®, the brand name for pirfenidone, is a prescription drug used for treating patients with idiopathic pulmonary fibrosis (IPF). It is approved by the United States Food and Drug Administration based on 3 clinical studies focused upon safety and effectiveness in 1400 patients. For more than 5 years, more than 170 of these patients were treated. It has been proven that Esbriet preserves lung function for patients with IPF. It is estimated that more than 50,000 patients worldwide have used Esbriet. The safety and effectiveness of Esbriet are still unknown among children. IPF is different from interstitial lung disease, which causes scarring of the lungs. Esbriet is primarily approved for IPF and slows the progression of the disease. The lung function loss cannot be restored. According to a 1-year clinical study, it was found that patients who took pirfenidone had better breathing capacity compared to patients who did not take the drug. There was a difference of 193 ml in terms of the forced vital capacity between the groups noted in the clinical study.¹

Read more about approved therapies for idiopathic pulmonary fibrosis

Usage of Esbriet

Esbriet is a drug that can treat mild to moderate IPF. IPF is a long-term disease that can cause fibrous scar tissue in the lungs. Patients may demonstrate symptoms of persistent cough, shortness of breath, and frequent infections. The number of patients with IPF is low, as it is a rare disease. On November 16, 2004, Esbriet was designated as an orphan drug. It is taken during mealtime and available in the form of 267 mg as capsules and 267, 543, and 801 mg as tablets. The dosage is generally increased over the period, as 267 mg is offered 3 times a day, then increased to 534 mg 3 times a day in the second week, and finally, 801 mg offered 3 times a day from the third week onward. Some of the side effects associated with the use of Esbriet are skin reactions, stomach issues, and changes in the liver enzymes. All doses are monitored by a physician and if required, changed to lower doses.²

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Credit: PubChem

Pharmacodynamic Properties of Esbriet

Esbriet inhibits the progression of fibrosis. It is a synthetic orally bioavailable pyridone compound. It is classified as an immunosuppressant, and its mechanism of action is not fully understood. In pre-existing animal models and in in vitro studies of pulmonary fibrosis, it was suggested that pirfenidone has antioxidant, antifibrotic, and anti-inflammatory properties. The antifibrotic effects of Esbriet are related to its anti-inflammatory effects and pulmonary levels of growth factors, chemokines, and cytokines. Pirfenidone reduces the production of a proinflammatory and profibrotic cytokine: transforming growth factor b1 (TGF-b1) as seen in the lungs of the animal models with pulmonary fibrosis. According to studies conducted in in vitro models, the differentiation induced by TGF-b1 of human lung fibroblasts into myofibroblasts was inhibited by pirfenidone. It prevents the excessive synthesis of extracellular matrix proteins and collagen. Pirfenidone has exhibited a dose-dependent prevention of TGF-b1 pro-proliferative effect. This effect of pirfenidone has been observed in primary lung myofibroblasts and type II alveolar epithelial cells. Pirfenidone inhibits TGF-b1 production, preventing the decline of the antifibrotic cytokine interferon-c, and suppresses interleukin (IL)-12p40. It also suppresses the elevation of pulmonary levels of lung basic fibroblast growth factor, stromal cell-derived factor-1a, IL18 in a pulmonary fibrosis murine model, and proliferation of fibroblasts in vitro.³

Pharmacokinetics and Metabolism of Esbriet

The linear pharmacokinetics of Esbriet varies between a 200-mg to 600-mg dose. The recommended maintenance dose is 801 mg; it is given after the single dose. The mean maximum plasma concentration (Cmax) of Esbriet is 7.9 mg/l in healthy adults. The time taken to reach the maximum concentration values is achieved between 30 to 60 minutes, as absorption occurs quickly. The median time to Cmax is 3.5 hours, as Cmax is lower when the drug is administered at fed versus fasting states.

Get detailed prescribing information on the Esbriet monograph page at MPR.

Esbriet is better tolerated with concomitant food intake at an absorption rate of 20%. It leads to a lower incidence of gastrointestinal adverse events. As per conducted clinical trials, it was found that 50% to 58% pirfenidone is bound to plasma protein albumin at concentrations of 1 mg/l to 1000 mg/l. It is metabolized by the cytochrome (CYP) P450 CYP1A2 enzyme along with other enzymes such as CYP2C19, CYP2C9, CYP2D6, and CYP2E, which contribute to metabolism. Esbriet is metabolized by 5-carboxy-pirfenidone and has a terminal elimination half-life of 2.4 hours with food and 2.9 hours without food at an 801-mg dose. Eighty percent of the administered dose is excreted through the urine as 5 carboxy-pirfenidone, and less than 1% of the dosage is recovered in the urine unaltered after 6 hours of administration. Patients with moderate liver function impairment have seen an increase in the bioavailability of pirfenidone by 60%. In patients suffering from mild to severe renal function impairment, no relevant clinical changes have been observed in pharmacokinetics.

The drug is contraindicated in patients with end-stage renal disease requiring dialysis or in patients with severe renal impairment where creatinine clearance is less than 30 ml per minute.⁴

Efficacy of Esbriet

Randomized, placebo-controlled phase III trials showed the efficacy of pirfenidone: ASCEND (NCT01366209) and CAPACITY (NCT00287716/NCT00287729). In CAPACITY clinical trials, patients with a forced vital capacity of more than 50% and with diffusing capacity for carbon monoxide greater than or equal to 35% were evaluated for the efficacy of pirfenidone. Patients in the ASCEND clinical trial with the diffusing capacity for carbon monoxide of 30% and forced vital capacity of 50% to 90% were evaluated for pirfenidone efficacy. Patients treated with the drug showed improved outcomes in terms of slowed disease progression, reduced lung function decline, and reduced mortality. The benefit of the treatment was observed in post hoc analysis for phase III clinical trials. Similar studies were conducted to understand the effect of pirfenidone on reducing forced vital capacity decline, and the findings were consistent in clinical trials. Differences in baseline characteristics and data analysis were observed, which also included long-term follow-up data. Overall, the clinical trials were conducted in a stringent manner, which does not necessarily affect real-world practices and patients with IPF.⁵

References

  1. How Esbriet® (pirfenidone) works & how it may help. Genentech. Accessed August 3, 2021.
  2. Esbriet. European Medicines Agency. Accessed August 3, 2021.
  3. Kim ES, Keating GM. Pirfenidone: a review of its use in idiopathic pulmonary fibrosis. Drugs. 2015;75(2):219-230. doi:10.1007/s40265-015-0350-9
  4. Xaubet A, Serrano-Mollar A, Ancochea J. Pirfenidone for the treatment of idiopathic pulmonary fibrosis. Expert Opin Pharmacother. 2014;15(2):275-281. doi:10.1517/14656566.2014.867328

Lancaster LH, de Andrade JA, Zibrak JD, et al. Pirfenidone safety and adverse event management in idiopathic pulmonary fibrosis.Eur Respir Rev. 2017;26(146):170057. doi:10.1183/16000617.0057-2017

Reviewed by Harshi Dhingra, MD, on 8/12/2021.

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