What was the optimal dose of pirfenidone in large studies on idiopathic pulmonary fibrosis?

Pirfenidone is an oral antifibrotic agent approved for the treatment of IPF and is a universally accepted treatment as per various guidelines. (4) Pirfenidone regulates the activity of the transforming growth factor (TGF)-beta and tumor necrosis factor (TNF)–alpha, inhibits fibroblast proliferation and collagen synthesis, and reduces cellular and histological markers of fibrosis. (5)

Pirfenidone 2,403 mg/day reduces disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with IPF. Treatment with pirfenidone 2,403 mg/day has acceptable tolerability and has improved survival rates in IPF patients. In the ASCEND trial, 278 IPF patients received treatment with 2,403 mg/day of pirfenidone for 52 weeks. The adherence rate was as high as 85%. This study included patients in the age group of 62 to 75 years. The results showed that decline in the forced vital capacity (FVC), an independent predictor of mortality, from baseline was 45.1% lesser compared with the control group. The mean decline from baseline in FVC was 235 ml in the pirfenidone group and 428 ml in the placebo group Pirfenidone 2,403 mg/day reduced the proportion of patients experiencing a decline in the 6-minute walk distance (P=0.04) and improved progression-free survival.2 Other studies, such as the CAPACITY, RECAP, and PASSPORT studies, have also used the 2,403 mg/day dose of pirfenidone and the patient's continued treatment for a long term. In the PASSPORT study, approximately one-third of IPF patients treated with pirfenidone in real-life settings were still under treatment 2 years after initiation. (4,6)

A real-world study has been reported from a premier tertiary care hospital in India regarding the tolerability and survival of pirfenidone in Indian patients with IPF. Two doses of pirfenidone were compared: a full dose (2,400 mg/day) and a reduced dose (<2,400 mg/day). Pirfenidone appeared to improve survival only with the full dose. Up to 42% of the study subjects tolerated the full dose of Pirfenidone. (7)

Have pirfenidone doses < 2,403 mg/day been used in studies? How does the lower dose compare with the 2,403 mg dose?

In the CAPACITY trial, IPF patients were randomized to receive a placebo and two different doses of pirfenidone, i.e. 1,197 mg/day and 2,403 mg/day. The decline in the FVC from baseline was significantly lesser with pirfenidone 2,403 mg/day compared with the dose of 1,197 mg/day. The treatment effect was evident by week 24. (5)

Figure1: Mean change from baseline in percentage predicted FVC

In the Indian study conducted at a premier tertiary care hospital in India, patients who received pirfenidone 2,400 mg/day had an 81% reduced risk of death compared with the lower dose.7

Figure 2: Trend toward significant improvement in survival in those who received full-dose with risk reduction in death by 81%

The current data strongly indicates that the reduction in the rate of FVC decline reported in patients with IPF treated with pirfenidone is dose-dependent and, therefore, may be affected by dose reduction. (4) Hence, it would be advisable to preferably prescribe the 2,403 mg/day dose of pirfenidone in IPF patients.

 Will long–term, continuous treatment with pirfenidone confer benefits in patients with IPF?

Analysis of data from pivotal Phase 3 trials in 1,247 IPF patients (555 from the ASCEND study and 692 from the CAPACITY studies) has proven that continued treatment with pirfenidone may be of benefit in patients with IPF who exhibit evidence of meaningful disease progression despite treatment. (4)

Treatment with pirfenidone for 1 year slowed the disease progression as measured by changes in the FVC, an independent predictor of mortality.4 Pirfenidone reduced the risk of death at 1 year by 48% compared with placebo. In addition, in the pooled population, the risk of treatment-emergent death due to IPF at 1 year was reduced by 68% in the pirfenidone group compared with the placebo group. (3)

Analysis of outcomes in patients who experienced a ≥10% absolute decline in %FVC between baseline and month 6 indicated that, during the subsequent 6-month period, just 5.9% of patients in the pirfenidone 2,403 mg/day group, compared with 27.9% of patients in the placebo group, experienced a second decline of ≥10% in %FVC, or death. The pooled analysis indicated that patients receiving pirfenidone had a lower risk of non-elective, respiratory-related hospitalization over the course of 1 year.8 In patients with at least one non-elective hospitalization, the death rates were lower in the pirfenidone-treated groups compared with the placebo-treated groups (17% vs 32%). (8)

In the long-term RECAP study, about 603 patients received a daily dose of pirfenidone 2,403 mg/day. The treatment duration ranged from 72 weeks to 163.3 weeks. The Kaplan-Meier estimate of survival was 69% at week 228 (4.4 years), and about 50% of patients were still under treatment at 5 years of follow-up. (3)

What is the data available on the safety of pirfenidone from various clinical trials?

An integrated safety analysis from five clinical trials demonstrated that pirfenidone is generally well tolerated. The extent of exposure to pirfenidone in the trials ranged from about 1 week to 9.9 years. There were fewer serious treatment-emergent adverse events (TEAEs) (20.5% vs 22.3% of patients) and fewer treatment-emergent deaths (2.2% vs 5.1% of patients) in the pirfenidone-treated group than in those receiving placebo. Gastrointestinal and skin-related events were the most common TEAEs, which tended to occur early during treatment and decreased over time. Parameters, such as body weight, that may be important for adjusting the pirfenidone dose to manage TEAEs and also maintain efficacy, have not been examined in detail. (4)

How should the gastrointestinal side effects of pirfenidone be managed?

Patients should be reminded to take pirfenidone with food to prevent or mitigate gastrointestinal side effects. Tablets/capsules may be divided across the course of a meal; taking the three capsules separately throughout the meal rather than all at once may help minimize adverse drug reactions. If symptoms persist, the pirfenidone dosage should be reduced to one to two tablets/ capsules, two to three times a day with food, with re-escalation to the recommended daily dose as tolerated. If symptoms still persist, patients may be instructed to interrupt treatment for 1–2 weeks to allow symptoms to resolve. Once the symptoms have resolved, it may be possible to re-challenge with pirfenidone. A slower re-escalation scheme (longer than the usual 2 weeks) may be effective in improving tolerability. The use of prokinetic agents or proton-pump inhibitors may be helpful for managing gastrointestinal symptoms in patients being treated with Pirfenidone. (3)

Are the outcomes from the real-world studies similar to the outcomes observed in controlled clinical trials?

In addition to long-term observational studies, a number of single-center studies have been published reporting the efficacy and tolerability of pirfenidone in a real-world setting. Generally, these single-center observational studies demonstrate that, in daily clinical practice, the efficacy and tolerability of pirfenidone are comparable with the data reported in controlled clinical trials. This is especially true with respect to disease stabilization and prevention of decline in pulmonary function.

References

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2. King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2083-92.

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5. Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, King TE Jr, Lancaster L, Sahn SA, Szwarcberg J, Valeyre D, du Bois RM; CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011 May 21;377(9779):1760-9.

6. Jouneau S, Gamez AS, Traclet J, Nunes H, Marchand-Adam S, Kessler R, Israël-Biet D, Borie R, Strombom I, Scalori A, Crestani B, Valeyre D, Cottin V. A 2-Year Observational Study in Patients Suffering from Idiopathic Pulmonary Fibrosis and Treated with Pirfenidone: A French Ancillary Study of PASSPORT. Respiration. 2019;98(1):19-28

7. Dhooria S, Agarwal R, Sehgal IS, Prasad KT, Muth V, Garg M, Bal A, Aggarwal AN, Behera D. A real-world study of the dosing and tolerability of pirfenidone and its effect on survival in idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis. 2020;37(2):148-157

8. Ley B, Swigris J, Day BM, Stauffer JL, Raimundo K, Chou W, Collard HR. Pirfenidone Reduces Respiratory-related Hospitalizations in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2017 Sep 15;196(6):756-761