The safety and tolerability of pirfenidone in Indian patients with idiopathic pulmonary fibrosis

Avinash Anil Nair; Richa Gupta; Prince James; Aparna Irodi; Devasahayam J Christopher; Balamugesh Thangagunam

doi:10.4103/cmi.cmi_89_21

ORIGINAL ARTICLE

Year : 2022 | Volume : 20 | Issue : 1 | Page : 27-31

The safety and tolerability of pirfenidone in Indian patients with idiopathic pulmonary fibrosis

Avinash Anil Nair¹, Richa Gupta¹, Prince James¹, Aparna Irodi², Devasahayam J Christopher³, Balamugesh Thangagunam³
¹ Department of Respiratory Medicine, Christian Medical College, Vellore, Tamil Nadu, India
² Department of Radiology, Christian Medical College, Vellore, Tamil Nadu, India
³ Department of Pulmonary Medicine, Christian Medical College, Vellore, Tamil Nadu, India

Date of Submission	23-Oct-2021
Date of Decision	16-Nov-2021
Date of Acceptance	01-Dec-2021
Date of Web Publication	04-Feb-2022

Correspondence Address:
Dr. Avinash Anil Nair
Department of Respiratory Medicine, Christian Medical College, Vellore, Tamil Nadu
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/cmi.cmi_89_21

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a form of progressive fibrosing interstitial lung disease with a poor prognosis. Pirfenidone is an oral antifibrotic agent used in the treatment of IPF, and it reduces the rate of decline of lung function. However, the tolerable dose and adverse effect profile appear to be different in the Indian population. Methodology: This prospective observational study was conducted in the Department of Pulmonary Medicine at a tertiary care center in India between January 2015 and June 2016. All adult patients diagnosed as IPF based on multidisciplinary discussion were enrolled. Subjects with active respiratory tract infection, other end-organ failures, and drugs interacting with Pirfenidone were excluded. Data collection was done with a predesigned questionnaire at baseline. Subsequently, they were followed up telephonically every week and in-person review at 3 and 6 months. Results: The cohort has 30 patients with a mean age of 60 years ± 4.5 (standard deviation 8.9). 80% did not tolerate the recommended total dose (40 mg/kg/day or 2400 mg/kg) and the median tolerated dose was 1800 mg/day (25–30 mg/kg). 75% reported adverse events, the most common being anorexia, and gastroesophageal reflux disease in gastrointestinal (GI) reaction, followed by a rash in dermatological reactions. All these adverse effects were mild to moderate and managed with supportive care or dose reduction. None of them were severe, causing cessation of therapy. Conclusion: Pirfenidone has a lower tolerable dose and predominantly GI adverse effects in our population, and if addressed early, it can prevent cessation of treatment and better quality of life for patients.

Keywords: Idiopathic pulmonary fibrosis, Pirfenidone, pulmonary fibrosis, side effects, tolerance, usual interstitial pneumonia

How to cite this article:
Nair AA, Gupta R, James P, Irodi A, Christopher DJ, Thangagunam B. The safety and tolerability of pirfenidone in Indian patients with idiopathic pulmonary fibrosis. Curr Med Issues 2022;20:27-31

How to cite this URL:
Nair AA, Gupta R, James P, Irodi A, Christopher DJ, Thangagunam B. The safety and tolerability of pirfenidone in Indian patients with idiopathic pulmonary fibrosis. Curr Med Issues [serial online] 2022 [cited 2023 Mar 22];20:27-31. Available from: https://www.cmijournal.org/text.asp?2022/20/1/27/337313

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrosing interstitial pneumonia of unknown cause.^[1] It has an abysmal prognosis with a median survival of 2–5 years.^[2] The mainstay of treatment has changed since the past decade after the US Food and Drug Administration approved antifibrotic drugs like Pirfenidone in 2014.^[3] Pirfenidone acts by inhibiting the transforming growth factor β and thereby prevents fibroblast proliferation in the alveolar interstitium.^[4],[5] It reduces the rate of decline of lung function and improves progression-free survival in IPF patients.^[6],[7] According to Assessment of Pirfenidone to Confirm Efficacy and Safety in IPF (ASCEND) and Clinical Studies Assessing Pirfenidone in IPF: Research of Efficacy and Safety Outcomes (CAPACITY) trials, the drug is generally well-tolerated and has few adverse events.^[6],[7] However, these studies did not include the Indian population. There is anecdotal evidence from other centers in India that the recommended dose of 2400 mg/day or 40 mg/kg/day is not tolerated by Indian patients and hence causing nonadherence to therapy, and the side effects caused more impairment to the quality of life of these patients with this debilitating disease.^[4],[8] Hence this study was aimed to evaluate the onset, severity, and management of adverse effects of Pirfenidone and to ascertain the maximum tolerable dose of the drug at the end of 6 months.

Methodology

Study design

This was a prospective observational study.

Study setting

We conducted this study at a tertiary care center in Southern India over 18 months from January 2015 to June 2016, after obtaining clearance from Institutional Review Board (IRB Min No: 9261 dated January 12, 2015).

Participants

All adult patients (18 years and above) diagnosed as IPF based on 2011 American Thoracic Society/European Respiratory Society consensus criteria, and the diagnosis was established after multi-disciplinary discussion consisting of pulmonologists, thoracic radiologists, Rheumatologists, and pathologists during the study period were included.^[1] Patients with active respiratory tract infections, including tuberculosis, chronic liver disease, chronic renal failure, heart failure, and who were on medications that interact with Pirfenidone were excluded from the study.

Study protocol

Each patient was started on Pirfenidone at the dose of 200 mg (one tablet) thrice daily, and the dose was increased weekly by adding three tablets additional per day till it reached 2400 mg/day or 40 mg/kg/day (whichever was lower).^[3] Patients who fulfilled inclusion criteria were interviewed using a predesigned structured questionnaire – baseline characteristics, comorbidities, the onset of adverse effect after initiation of drug – severity, and therapy required were noted. The patients were followed up via telephonic interview every week by the principal investigator, and details regarding any adverse effects or intolerance were noted, and corrective measures were advised as in [Table 1]. There were also two in-person follow-ups at 3 months and 6 months, during which Chest X-ray and pulmonary function tests were also done as part of standard treatment follow-up protocol. According to Common Terminology Criteria for Adverse Effects, the adverse events were graded as mild, moderate, and severe by the National Institute of Health.^[10] They were managed as per standard procedure either by supportive therapy, dose reduction or nonescalation, or cessation of therapy.

Table 1: General instructions and management of various adverse events

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Sample size

We calculated the sample size of 30 with a precision of around 17.5%, with a 95% confidence interval (CI), based on present literature, with a prevalence of adverse events of 40%.^[6]

Statistical methods

For the statistical analysis, the data were entered using EPI DATA software (EpiData Classic, Data Management and basic Statistical Analysis System. Odense Denmark, EpiData Association). The summary statistic is used for reporting demographic and clinical characteristics. All categorical variables were reported using frequencies and percentages and continuous variables in terms of mean ± standard deviation; all the statistical analyses were performed using Statistical Package for Social Sciences (SPSS) for Windows, version 16.0, (Chicago, Illinois, USA).

Results

During the 18-month study period, we recruited 30 patients who fulfilled the inclusion criteria. Our patients were predominantly males (63%) and presented with complaints of cough (100%), dyspnoea on exertion (93%). Clinical examination revealed hallmark findings of IPF like clubbing (90%) and basal Velcro crackles (100%). Eighteen percent of cases had prior empirical antitubercular therapy without microbiological or histopathological evidence of tuberculosis. The baseline characteristics are described in detail in [Table 2]. Only 20% of patients could tolerate the maximum recommended dose; the rest required dose reduction, or the dose could not be escalated as per the weekly schedule. The median tolerated dose by our patients at the end of 6 months was 1800 mg/day, which equates to 25–30 mg/kg/day. Systemic adverse effects were noted in (84%; n = 25) of cases with anorexia (40%; n = 10), gastroesophageal reflux disease (GERD) (36%; n = 9) and abdominal distension (8%, n = 2) being the most common. Only (16%; n = 4) had a rash, the only dermatological side effect noted in the study group. Adverse event profile and treatment measures are described in [Table 3]. The severity of adverse effects was mild to moderate and was managed as per the standard protocol described in [Table 1].

Table 2: Baseline characteristics and demographics of participants (n=30)

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Table 3: Adverse events in the study group

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Discussion

Our study found that 84% of patients experienced systemic side effects within 6 months after initiation of Pirfenidone, which was much higher than that is observed by Cottin, Taguchi et al., and Cameli et al.^{[5],[11],[12],[13]} In contrast to Western data [summarised in [Table 4]], anorexia (40%) and GERD (36%) were the most common gastrointestinal (GI) side effects. The incidence of dermatological side effects during the initiation phase of the drug in other studies is significant, but in our study group, the only mild rash was seen in only 16% of patients and settled with supportive therapy, compared to 28% in other studies, where it was significant enough to stop the drug. This finding may suggest a geographical difference in the dermatological adverse events.^[7],[9],[14] Due to significant adverse events, 13%–19% of patients had to stop treatment with Pirfenidone as in Arai et al.^[4] However, none of our patients required cessation of the drug. This finding highlights that patient education, early recognition, and adverse event management significantly improve therapy compliance and prevent discontinuation. In our study, the maximum tolerable dose of Pirfenidone was found to be 25–30 mg/kg/day, which is lower than the dose (40 mg/kg/day) recommended in ASCEND and CAPACITY trials.^[6],[7] However, few trials from Japan Uehara et al., show a tolerable range similar to our study-1200–1800 mg/kg/day.^[15] To minimize the adverse events, recent literature suggests that the dose of Pirfenidone should be based on body surface area. These findings highlight the fact that there may be ethnic differences in drug tolerability and adverse effect profile of Pirfenidone.

Table 4: Adverse events profile – various studies across the globe

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The limitation of our study was that it was a single-center study in Southern India with a relatively small number of patients. In addition, we could not study the assess the efficacy of Pirfenidone at a lower dose tolerated because the usual change in lung function is measured at the end of 1 year and our follow-up ended at 6 months, and many of our patients were unable to come for further follow up because of the debilitating nature of the disease.

Conclusion

Indian IPF patients tolerate lower doses of Pirfenidone than the West, and most of them have GI adverse effects like anorexia and GERD, which need supportive care and dose reduction. Further studies are required to elucidate the clinical efficacy of a lower dose of the drug in IPF.[17]

Research quality and ethics statement

The authors of this manuscript declare that this scientific work complies with reporting quality, formatting, and reproducibility guidelines set forth by the EQUATOR Network. The authors also attest that this clinical investigation was determined to require Institutional Review Board/Ethics Committee review, and the corresponding protocol/approval number is 9261, dated January 12, 2015. We also certify that we have not plagiarized the contents in this submission and have done a plagiarism check.

Acknowledgment

We would like to thank Mrs. Deepa, our clinical research coordinator, Mrs. Sudha, and Mrs. Nadiya, our department secretaries, for their help and support in this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: Idiopathic pulmonary fibrosis: Evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788-824.
2.	Ley B, Ryerson CJ, Vittinghoff E, Ryu JH, Tomassetti S, Lee JS, et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med 2012;156:684-91.
3.	Voice FDA. Two FDA Drug Approvals for Idiopathic Pulmonary Fibrosis (IPF) \| FDA Voice. Available from: https://blogs.fda.gov/fdavoice/index.php/2014/10/two-fda-drug-approvals-for-idiopathic-pulmonary-fibrosis-ipf/. [Last accessed on 2018 Jan 12].
4.	Arai T, Inoue Y, Sasaki Y, Tachibana K, Nakao K, Sugimoto C, et al. Predictors of the clinical effects of Pirfenidone on idiopathic pulmonary fibrosis. Respir Investig 2014;52:136-43.
5.	Cottin V. The role of Pirfenidone in the treatment of idiopathic pulmonary fibrosis. Respir Res 2013;14 Suppl 1:S5.
6.	Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): Two randomized trials. Lancet 2011;377:1760-9.
7.	King TE, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al. A phase 3 trial of Pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2083-92.
8.	Richeldi L, Rubin AS, Avdeev S, Udwadia ZF, Xu ZJ. Idiopathic pulmonary fibrosis in BRIC countries: The cases of Brazil, Russia, India, and China. BMC Med 2015;13:237.
9.	Lynch DA, Sverzellati N, Travis WD, Brown KK, Colby TV, Galvin JR, et al. Diagnostic criteria for idiopathic pulmonary fibrosis: A fleischner society white paper. Lancet Respir Med 2018;6:138-53.
10.	Common Terminology Criteria for Adverse Events (CTCAE). Available from:https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_40. [Last accessed on 2021 Nov 12].
11.	Bargagli E, Piccioli C, Rosi E, Torricelli E, Turi L, Piccioli E, et al. Pirfenidone and Nintedanib in idiopathic pulmonary fibrosis: Real-life experience in an Italian referral centre. Pulmonology 2019;25:149-53.
12.	Cottin V, Maher T. Long-term clinical and real-world experience with Pirfenidone in the treatment of idiopathic pulmonary fibrosis. Eur Respir Rev 2015;24:58-64.
13.	Cameli P, Refini RM, Bergantini L, d'Alessandro M, Alonzi V, Magnoni C, et al. Long-term follow-up of patients with idiopathic pulmonary fibrosis treated with Pirfenidone or nintedanib: A real-life comparison study. Front Mol Biosci 2020;7:581828.
14.	Taguchi Y, Ebina M, Hashimoto S, Ogura T, Azuma A, Taniguchi H, et al. Efficacy of Pirfenidone and disease severity of idiopathic pulmonary fibrosis: Extended analysis of phase III trial in Japan. Respir Investig 2015;53:279-87.
15.	Uehara M, Enomoto N, Oyama Y, Suzuki Y, Kono M, Furuhashi K, et al. Body size-adjusted dose analysis of Pirfenidone in patients with interstitial pneumonia. Respirology 2018;23:318-24.
16.	Cottin V. Treatment of progressive fibrosing interstitial lung diseases: A milestone in the management of interstitial lung diseases. Eur Respir Rev 2019;28:190109.
17.	Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010;35:821-9.