Pirfenidone

Pirfenidone: A Review of Its Use in Idiopathic Pulmonary Fibrosis

Esther S. Kim • Gillian M. Keating © Springer International Publishing Switzerland 2015

Abstract

Pirfenidone (Esbriet®) is an orally administered, synthetic, pyridone compound that is approved for the treatment of adults with mild to moderate idiopathic pul- monary fibrosis (IPF) in the EU, and for the treatment of IPF in the USA. This article summarizes pharmacological, effi- cacy and tolerability data relevant to the use of pirfenidone in these indications. In the randomized, double-blind, placebo- controlled, multinational CAPACITY trials in patients with mild to moderate IPF, a significant reduction in the rate of decline in forced vital capacity (FVC) was seen with pirfe- nidone versus placebo in study 004 but not in study 006. Pirfenidone also reduced the rate of decline in FVC to a significantly greater extent than placebo in the randomized, double-blind, multinational ASCEND trial in this patient population. In addition, pirfenidone showed a significant treatment effect on the 6-min walking test distance and progression-free survival in the ASCEND trial and in a pooled analysis of the CAPACITY trials. Pirfenidone had a manageable tolerability profile in all three studies. Gastro- intestinal and skin-related events (e.g. nausea, rash, photo- sensitivity reaction), which were the most commonly occurring treatment-emergent adverse events, were gener- ally mild to moderate in severity. In addition, a prespecified mortality analysis across all three studies demonstrated a significant reduction in IPF-related and all-cause mortality with pirfenidone. In conclusion, oral pirfenidone is a valu- able agent for use in patients with IPF.

1 Introduction

Idiopathic pulmonary fibrosis (IPF) is a specific fibrosing form of interstitial pneumonia that is chronic, progressive and of an unknown cause [1]. It is limited to the lungs, occurs primarily in older adults and is associated with histological and/or radiological characteristics of usual interstitial pneumonia (UIP) [1]. Studies in Europe suggest an annual incidence of 0.22–7.4 cases per 100,000 and a prevalence of 1.25–23.4 cases per 100,000 in the popula- tion [2]. The prognosis is poor, with a median survival time estimated at 2–5 years from the time of diagnosis [3]. The 5-year survival rate is approximately 20 % [4], and the mortality burden associated with IPF is higher than that of some cancers [1, 5].

The underlying cause of the fibrotic response in IPF is unknown, but several potential risk factors have been described (e.g. cigarette smoking, environmental expo- sures, gastroesophageal reflux, genetic factors and micro- bial agents) [1]. The understanding of IPF pathogenesis has shifted over time, and this has affected the approach to treatment [6]. In the past, IPF was thought of as an inflammation-driven disorder [6]. Therefore, conventional treatments (e.g. corticosteroids and immunomodulatory agents) were based on the concept of preventing fibrosis by suppressing inflammation [7]. However, growing evidence has led to the understanding that inflammation is not a major histopathological finding in UIP and that fibroblast foci (i.e. actively proliferating fibroblasts and myofibro- blasts) develop early in UIP [8].This has led to the current hypothesis of ongoing alveolar epithelial cell injury leading to abnormal wound healing and fibrosis in IPF [7], and targeting mechanisms and mediators involved in tissue fibrosis has become an important strategy of IPF treatment [6].

Pirfenidone (Esbriet®) is a pyridone compound indi- cated for the treatment of IPF in various countries world-wide [9], including those of the EU where it is the first drug approved for use in adults with mild to moderate IPF [10, 11], and including the USA where it is one of two drugs approved for use in patients with IPF [12, 13].This article summarizes pharmacological, efficacy and tolerability data relevant to the use of pirfenidone in these indications.

2 Pharmacodynamic Properties

Pirfenidone is an orally bioavailable, synthetic, pyridone compound [14] that inhibits the progression of fibrosis [15]. It is classified as an immunosuppressant [11]. Although the mechanism of action is not fully understood, existing data from in vitro studies and animal models of pulmonary fibrosis suggest that pirfenidone has antifibrotic, anti-inflammatory and antioxidant properties [11, 16]. The antioxidant properties of pirfenidone may contribute to its anti-inflammatory effects, and these in turn may account for some of pirfenidone’s antifibrotic effects [16, 17].

The antifibrotic properties of pirfenidone were mainly attributed to its effects on pulmonary levels of various cytokines, growth factors and chemokines [16]. Pirfenidone reduced the production of transforming growth factor-b1 (TGF-b1), a profibrotic and pro-inflammatory cytokine, in the lungs of animal models of pulmonary fibrosis [16, 18]. In vitro, pirfenidone inhibited the TGF-b1-induced differ- entiation of human lung fibroblasts into myofibroblasts and thereby prevented the excessive synthesis of collagen and extracellular matrix proteins [15]. In primary alveolar epi- thelial type II cells and primary lung myofibroblasts iso- lated from the lung parenchyma of IPF patients, pirfenidone exhibited dose-dependent prevention of TGF-b1’s pro- proliferative effect (data available as an abstract) [19]. Pirfenidone is thought to inhibit the production of TGF-b1 by preventing the decline of interferon-c, an antifibrotic cytokine, through the suppression of interleukin (IL)-12p40 [16]. In addition, pirfenidone suppressed the proliferation of fibroblasts in vitro [20] and suppressed the elevation of pulmonary levels of lung basic-fibroblast growth factor, IL- 18 and stroma cell derived factor (SDF)-1a in a murine model of pulmonary fibrosis [16].

The anti-inflammatory properties of pirfenidone were attributed to its regulation of pulmonary inflammatory cytokines and inflammatory cells [20]. Pirfenidone inhib- ited the release of proinflammatory cytokines such as IL- 1b, IL-6, tumour necrosis factor (TNF)-a and platelet- derived growth factor (PDGF) in animal models of pul- monary fibrosis [16, 21, 22]. In alveolar macrophages from the bronchoalveolar lavage of patients with IPF or idio- pathic nonspecific interstitial pneumonia, pirfenidone was seen to suppress various cytokines including IL-1b and TNF-a (data available as an abstract) [23]. Of note, some proinflammatory cytokines such as TNF-a and PDGF are also profibrotic cytokines [24]. Pirfenidone also enhanced the production of IL-10, an anti-inflammatory cytokine, in a murine model of endotoxic shock [25]. In addition, pirfenidone inhibited monocyte chemoattractant protein (MCP)-1 in mice [16] and inhibited the accumulation of various inflammatory cells including lymphocytes, mac- rophages and neutrophils in hamsters [18].

The antioxidant properties of pirfenidone were attributed to its ability to scavenge reactive oxygen species (ROS), including hydroxyl radicals and superoxide anions, as shown in several in vitro studies [22, 24, 26]. In pulmonary fibrosis, the activation of alveolar macrophages and the phagocytosis of neutrophils result in the release of ROS, which can decrease the function of alveolar-capillary beds through lipid peroxidation and cause cellular injury [18, 24, 26]. Malonaldehyde, the end-product of lipid peroxidation, has been shown to stimulate collagen synthesis [22]. In addition, neutrophil degranulation results in the release of myeloperoxidase, which catalyses the reaction of hydrogen peroxide with chloride to form hypochlorous acid, a cyto- toxic compound that damages the alveolar architecture [17, 18]. Pirfenidone scavenged ROS and inhibited lipid per- oxidation and malonaldehyde activity in vitro [22] and in animal models of pulmonary fibrosis [17].

3 Pharmacokinetic Properties

3.1 Absorption and Distribution

Administration of pirfenidone in a fed state versus a fasted state reduces overall exposure, peak plasma concentration (Cmax) values and the rate of absorption [11, 12, 20]. In healthy older adults (aged 50–66 years) administered a single oral dose of pirfenidone 801 mg, the area under the plasma concentration-time curve (AUC) for pirfenidone in a fed state was approximately 80–85 % of the AUC for pirfenidone in a fasted state [27]. In addition, mean Cmax was reduced by 50 % when administered with food [11]. Following a single dose of pirfenidone 801 mg with food, a mean pirfenidone Cmax of 7.9 lg/mL was reached in a median 3.5 h [27]. Pirfenidone binds mainly to serum albumin in humans [11, 12]. In clinical studies, pirfenidone had an overall mean binding of 50–58 % [11, 12]. Pirfenidone was not widely distributed to tissues; results of a pooled population pharmacokinetic analysis showed an apparent oral steady- state volume of distribution of &70 L [11, 20].

3.2 Metabolism and Elimination

Pirfenidone is metabolized predominantly by the cyto- chrome P450 (CYP) pathway [11, 12]. Approximately 70–80 % of pirfenidone is metabolized by CYP1A2. Pirf- enidone is also metabolized by CYP2C9, CYP2C19, CYP2D6 and CYP2E1, but to a lesser extent [11, 12].
The mean terminal elimination half-life of pirfenidone after the administration of a single dose of 801 mg in healthy older adults was approximately 2.4 h with food and 2.9 h without food [27]. The mean apparent oral clearance of pirfenidone was 13.8 L/h with food and 11.8 L/h without food [27]. Within 24 h of oral administration, approxi- mately 80 % of the pirfenidone dose was excreted in urine [11, 27]. Pirfenidone was excreted predominantly ([95 %) as 5-carboxy-pirfenidone, the primary metabolite of pirfe- nidone, with \1 % of pirfenidone excreted unchanged and \0.1 % excreted as other metabolites [11, 20, 27].

3.3 Special Patient Populations

Pirfenidone should be used with caution in patients with mild to moderate liver impairment because of the potential

for increased pirfenidone exposure [11, 12]. The EU summary of product characteristics (SPC) states that pirf- enidone is contraindicated in patients with severe liver impairment or end-stage liver disease [11], and the US prescribing information states that pirfenidone is not rec- ommended in patients with severe hepatic impairment [12]. Liver function should be monitored during pirfenidone treatment, especially if CYP1A2 inhibitors are used con- comitantly (Sect. 3.4), and dose adjustments or treatment discontinuation may be necessary for patients with elevated levels of ALT, AST or bilirubin [11, 12].

The EU SPC states that the dose of pirfenidone does not need to be adjusted in patients with mild to moderate renal impairment, although treatment with pirfenidone is con- traindicated in patients with severe renal impairment [creatinine clearance of \30 mL/min (\1.80 L/h)] or end- stage renal disease requiring dialysis [11]. The US pre- scribing information states that pirfenidone should be used with caution in patients with mild, moderate or severe renal impairment, and that treatment with pirfenidone is not recommended in patients with end-stage renal disease requiring dialysis [12].Age, body size, gender and race do not have a clinically relevant effect on pirfenidone pharmacokinetics [11, 12]. No dose adjustments are necessary for elderly patients [11, 12], and there is no relevant use of pirfenidone in paediatric patients [11].

3.4 Potential Drug Interactions

Given that pirfenidone is metabolized predominantly by CYP1A2 and to a lesser extent by CYP2C9, CYP2C19, CYP2D6 and CYP2E1, there is potential for interactions between pirfenidone and inhibitors or inducers of these enzymes [11, 12].The EU SPC states that the concomitant use of flu- voxamine, a strong CYP1A2 inhibitor with inhibitory effects on CYP2C19, CYP2C9 and CYP2D6, is contra- indicated during pirfenidone therapy [11]. The US pre- scribing information does not recommend the concomitant use of pirfenidone and strong CYP1A2 inhibitors such as enoxacin or fluvoxamine [12]. However, if fluvoxamine or other strong CYP1A2 inhibitors are the only drug of choice, the US prescribing information recommends reducing the dose of pirfenidone to one capsule three times daily [12].

Ciprofloxacin is a moderate CYP1A2 inhibitor [11, 12]. If the use of ciprofloxacin 750 mg twice daily cannot be avoided, the dosage of pirfenidone should be reduced to 1,602 mg/day [11, 12]. The EU SPC states that pirfenidone should be used with ciprofloxacin 250 or 500 mg once or twice daily with caution [11], and the US prescribing information states that patients should be monitored closely when a ciprofloxacin dosage of 250 or 500 mg once daily is administered [12].

According to the EU SPC, other moderate CYP1A2 inhibitors such as amiodarone and propafenone should be used with caution, and grapefruit juice should be avoided during treatment [11]. In addition, the EU SPC states that special care should be exercised if CYP1A2 inhibitors and potent inhibitors of one or more other isoenzymes involved in pirfenidone metabolism are used together [11]. The US prescribing information states that agents that are moderate or strong inhibitors of both CYP1A2 and other CYP iso- enzymes involved in pirfenidone metabolism should be withdrawn prior to, and avoided during, pirfenidone treat- ment [12].

Strong CYP1A2 inducers should be discontinued prior to, and avoided during, pirfenidone treatment [11, 12]. Smoking, which has strong potential to induce CYP1A2, should be avoided during pirfenidone therapy [11]. Drugs like rifampicin that potently induce both CYP1A2 and other CYP isoenzymes should also be avoided. Omepra- zole is a moderate CYP1A2 inducer and can theoretically lower pirfenidone exposure [11].

4 Therapeutic Efficacy

This section focuses on results from three randomized, double-blind, placebo-controlled, multinational, phase III trials (Table 1). Two of the trials (study 004 and study 006) were part of the CAPACITY (Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes) programme [14]. They were concurrent and nearly-identical trials that were designed to examine the efficacy of pirfenidone in patients with IPF and mild to moderate physiological impairment [14]. ASCEND (Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis), the third trial, also examined the efficacy of pirfenidone in patients with mild to moderate IPF [28]. Earlier studies, including compassionate-use studies [29, 30] and studies in Japanese patients [31, 32], also examined the effectiveness of pirfenidone in IPF. The findings of these trials are consistent with those of the phase III trials, but are not discussed further here.

Eligible patients in CAPACITY studies 004 and 006 [14] and in ASCEND [28] were randomized to receive pirfenidone 2,403 mg/day (the approved dosage) or pla- cebo for 72 [14] or 52 [28] weeks. In all three studies, pirfenidone was administered daily with food in three divided doses and titrated up to the full dose over 2 weeks [14, 28]. CAPACITY study 004 also included a pirfeni- done 1,197 mg/day treatment arm (n = 87) [14]. Out- comes in the 1,197 mg/day group were reported as being intermediate to those of the pirfenidone 2,403 mg/day and placebo groups [14]. Although pirfenidone can be titrated up and down in specific cases, the 1,197 mg/day treatment arm is not discussed further as it is not specifically men- tioned as a recommended dosage in the EU SPC [11].Study endpoints are summarized in Table 1. Primary efficacy analyses used a rank analysis of covariance (ANCOVA) model, and all efficacy analyses were per- formed in the intent-to-treat population [14, 28].

4.1 Phase III Trials

4.1.1 CAPACITY

In CAPACITY, percentage predicted FVC declined to a significantly smaller extent from baseline to week 72 with pirfenidone than with placebo in study 004, although no significant difference was seen between pirfenidone and placebo in study 006 (Table 2) [14]. This difference in FVC outcomes between the two studies may have been partly attributable to baseline imbalances. For example, numerically more patients in study 006 than study 004 had been diagnosed with IPF in the past year (Table 1), and patients receiving placebo in study 006 had a numerically higher incidence of obstructive airway disease [14]. Ana- lysis of pooled data from studies 004 and 006 showed a significant pirfenidone treatment effect for this endpoint (Table 2) [14].

In terms of percentage predicted FVC, a significant (p \ 0.05) treatment effect was seen with pirfenidone versus placebo from weeks 24 to 72 in study 004 and from weeks 12 to 48 in study 006 [14]. Repeated-measures analysis over all assessment time points showed a signifi- cant (p B 0.007 vs. placebo) treatment effect with pirfe- nidone in both studies [14].

Results were mixed for the secondary endpoints in the CAPACITY studies [14]. Pirfenidone significantly reduced the proportion of patients with an FVC decline of C10 % (Table 2) and significantly (p = 0.023) prolonged pro- gression-free survival (PFS) [hazard ratio (HR) 0.64; 95 % CI 0.44–0.95] compared with placebo in study 004, but not in study 006. By contrast, pirfenidone significantly reduced the decline in 6-min walking test (6MWT) distance com- pared with placebo in study 006, but not in study 004 (Table 2). Significant between-group differences were not seen in either study for dyspnoea, percentage predicted haemoglobin-corrected carbon monoxide diffusing capac- ity (DLCO) or worst peripheral oxygen saturation (SpO2) during 6MWT (Table 2). Analysis of pooled data from studies 004 and 006 showed a significant pirfenidone treatment effect on FVC decline of C10 % (Table 2), PFS (HR 0.74; 95 % CI 0.57–0.96) [p = 0.025] and 6MWT
distance (Table 2). In the pooled analysis, on-treatment IPF-related mortality was significantly (p = 0.03) lower with pirfenidone than with placebo (3 vs. 7 %) [HR 0.48; 95 % CI 0.24–0.95], with no significant between-group difference in overall all-cause mortality (8 vs. 10 %). Treatment adherence (i.e. proportion of patients receiving C80 % of scheduled doses) was 88 % with pirfenidone and 93 % with placebo in the CAPACITY studies [14].

4.1.2 ASCEND

In the ASCEND study, the percentage predicted FVC declined to a significantly smaller extent (p \ 0.001) with pirfenidone than with placebo at week 52 [28]. A signifi- cant relative reduction of 47.9 % in the proportion of patients with a decline of C10 % in percentage predicted FVC or death was seen in the pirfenidone versus the pla- cebo group (Table 3). No decline in percentage predicted FVC was seen in 22.7 % of pirfenidone recipients and in 9.7 % of placebo recipients. Supportive analyses of the primary endpoint revealed a significantly smaller mean decline from baseline in FVC with pirfenidone than with placebo (-235 vs. -428 mL; p \ 0.001) [28].

The mean decline in the 6MWT distance from baseline to week 52 was significantly (p = 0.036) smaller with pirfenidone than with placebo [28]. In addition, pirfenidone significantly prolonged PFS (HR 0.57; 95 % CI 0.43–0.77) [Table 3]. Significant between-group differences were not seen for dyspnoea. No significant difference was seen between pirfenidone and placebo recipients in all-cause mortality (4.0 vs. 7.2 %) or IPF-related mortality (1.1 vs. 2.5 %). Treatment adherence was 85.3 % with pirfenidone and 92.4 % with placebo in ASCEND [28].

4.1.3 Pooled Analysis

A prespecified analysis pooling data from the CAPACITY and ASCEND trials showed that pirfenidone significantly (p B 0.01) reduced both treatment-emergent IPF-related mortality and all-cause mortality compared with placebo [28]. At 1 year, all-cause mortality was 3.5 % with pirfe- nidone and 6.7 % with placebo (HR 0.52; 95 % CI 0.31–0.87), and treatment-emergent IPF-related death was 1.1 and 3.5 % in the corresponding treatment groups (HR 0.32; 95 % CI 0.14–0.76) [28].

4.2 Extension Study

RECAP (study 012; NCT00662038) is an ongoing open- label extension study for patients who completed one of the CAPACITY studies or the ASCEND study [33–35]. The primary objective of RECAP is the evaluation of pirfeni- done’s long-term safety (Sect. 5.2) [35, 36]. Inclusion criteria for RECAP includes receipt of C80 % of the assigned study treatment and completion of the final fol- low-up visit in a qualifying study (CAPACITY or ASCEND) [33, 35]. Eligible patients receive pirfenidone 2,403 mg/day with the same drug schedule as that used in the CAPACITY studies [33].

An interim analysis of RECAP (cut-off date of 14 April 2010) examined the lung function and survival of patients who had previously received placebo in CAPACITY and who were newly starting treatment with pirfenidone in RECAP [36]. Patients were included if their baseline FVC and DLCO at the start of RECAP met CAPACITY enrol- ment criteria (n = 178). Results of this interim analysis showed percent predicted FVC and overall survival out- comes that were consistent with those seen in previous randomized trials of pirfenidone in IPF patients. At week 60 in RECAP, the mean change in percent predicted FVC was -5.9 %, 16.3 % of patients had a decline in FVC of C10 % and mortality was 3.4 % [36].

4.3 Real-World Studies

Several studies examined the efficacy of oral pirfenidone in patients with IPF in real-world settings. Studies included 31–308 patients and, where specified, were of prospective [37–39] or retrospective [40–43] and multicentre [39–41] and ASCEND [28] trials, supplemented by long-term [33, 46] and real-world tolerability data [11, 38, 39, 41–44, 47].

Interim analysis data from the nursing patient support programme revealed that after 6 months of pirfenidone therapy, adherence (C80 % of the therapeutic dose) was at 83 % and compliance (full dose) was at 78 % [38]. At month 6, persistency (patients continuing treatment) was at 81 % [38]. In other studies, 95 % of patients took C80 % of pirfenidone doses [44] and 89 % of patients took pirf- enidone at the prescribed dosage of 2,403 mg/day [43].

5.1 General Adverse Event Profile

The most commonly reported adverse events were gastro- intestinal and skin-related events [14, 28, 46, 47]. Gener- ally, these events were of mild to moderate severity, reversible and infrequently led to treatment discontinuation [14, 28, 46]. In CAPACITY studies 004 and 006, at least one treat- ment-emergent adverse event was reported in 98.6 % of pirfenidone 2,403 mg/day recipients and in 97.7 % of placebo recipients [33]. In a pooled analysis of these trials, all-grade treatment-emergent adverse events occurring in C10 % of patients (and in 1.5-fold more pirfenidone 2,403 mg/day than placebo recipients) included nausea, rash, dyspepsia, dizziness, vomiting, photosensitivity reaction, anorexia, arthralgia, insomnia and abdominal distension (Fig. 1) [14]. Grade 3 or 4 gastrointestinal and skin-related adverse events occurring in the pooled pirfe- nidone 2,403 mg/day group and the pooled placebo group included nausea (1.7 vs. 0.6 % of patients), diarrhoea (0.6 vs. 0 %), dyspepsia (0.3 vs. 0.6 %), vomiting (0.3 vs. 0 %), photosensitivity reaction (0.9 vs. 0.3 %) and rash (0.6 vs. 0 %) [33]. Serious treatment-emergent adverse events occurred in 33 % of patients in the pooled pirfenidone 2,403 mg/day group and in 31 % of patients in the pooled placebo group [14]. The most commonly occurring serious treatment-emergent adverse event was worsening IPF (7.5 % with pirfenidone 2,403 mg/day and 8.0 % with placebo in CAPACITY 004; 7.6 % with pirfenidone 2,403 mg/day and 9.8 % with placebo in CAPACITY 006) [14].

Incidence (% of patients)

Fig. 1 Incidence of treatment-emergent adverse events of any grade occurring in C10 % of patients, with a C1.5-fold greater incidence in pirfenidone 2,403 mg/day recipients than with placebo recipients. Results of a a pooled analysis of the CAPACITY trials [14] and b the ASCEND trial [28].

In ASCEND, all-grade treatment-emergent adverse events occurring in C10 % of patients (and in 1.5-fold more pirfenidone 2,403 mg/day than placebo recipients) included nausea, rash, dyspepsia, anorexia, decrease in weight, gastroesophageal reflux and insomnia (Fig. 1) [28]. Grade 3 gastrointestinal adverse events occurred in 5.4 % of patients receiving pirfenidone compared with 1.4 % of patients receiving placebo, and grade 3 skin-related adverse events occurred in 1.8 and 0.4 % of patients in the corresponding treatment groups. There were no reports of grade 4 gastrointestinal or skin-related adverse events.

Serious treatment-emergent adverse events occurred in 19.8 % of pirfenidone recipients and in 24.9 % of placebo recipients. The most commonly occurring serious treat- ment-emergent adverse event was worsening IPF (2.5 % with pirfenidone and 9.7 % with placebo), which was counted as an adverse event as per study protocol [28].

In the CAPACITY studies, discontinuation rates because of treatment-emergent adverse events were 15 % in the pooled pirfenidone 2,403 mg/day group and 9 % in the pooled placebo group [14]. The most common treat- ment-emergent adverse event leading to treatment with- drawal in both groups (3 vs. 3 %) was IPF worsening [14]. Similarly in ASCEND, discontinuation rates because of treatment-emergent adverse events were 14.4 % in the pirfenidone group and 10.8 % in the placebo group, and the most common treatment-emergent adverse event leading to treatment withdrawal in both groups (1.1 vs. 5.4 %) was IPF worsening [28].

In the CAPACITY studies, 4 % of patients in the pooled pirfenidone group developed increased ALT or AST levels [3 9 the upper limit of normal (ULN) compared with 0.6 % of patients in the pooled placebo group [14]. Sub- stantial laboratory abnormalities (grade 4 or a change of three grades) included hyperglycaemia (1 % in pooled pirfenidone 2,403 mg/day group vs. 0.9 % in pooled pla- cebo group), hyponatraemia (1 vs. 0 %), hypophosphata- emia (2 vs. 0.9 %) and lymphopenia (1 vs. 0 %) [14]. In ASCEND, 2.9 % of patients in the pirfenidone group developed increased ALT or AST levels C3 9 ULN compared with 0.7 % of patients in the placebo group [28]. In all trials, the increases in transaminase levels were reversible and without clinical sequelae [14, 28].

5.2 Long-Term Tolerability

Pirfenidone is generally well tolerated long term in patients with IPF, according to interim data (cut-off date of 29 April 2011) from an integrated population analysis in which the median daily dosage of pirfenidone was 2,257 mg (range 25–3,600 mg) and median duration of exposure to pirfenidone was 2.6 years (range 1 week–7.7 years) [33]. The population analysed consisted of CAPACITY participants who received either pirfenidone 1,197 or 2,403 mg/day (n = 432), RECAP participants newly initiating pirfenidone 2,403 mg/day after placebo randomization in CAPACITY (n = 274) and study 002 participants who received pirfenidone (n = 83). The inte- grated analysis interim data discussed here did not include ASCEND data [33].

Study 002 (NCT00080223) [35], an ongoing, open- label, compassionate-use study being conducted in the USA, included patients with either IPF or secondary pul- monary fibrosis who were treated with oral pirfenidone in three equally divided daily doses after a 2-week dose titration period [33]. Following protocol amendment 1 (15 December 2003), secondary pulmonary fibrosis was elim- inated from the inclusion criteria, and the integrated pop- ulation included only two patients with secondary pulmonary fibrosis. Patients who enrolled in study 002 prior to protocol amendment 2 (15 September 2005) received oral pirfenidone 40 mg/kg/day (up to 3,600 mg/ day). Patients who enrolled after protocol amendment 2 received oral pirfenidone at a target maintenance dosage of 2,403 mg/day [33].

In the integrated population, at least one treatment- emergent adverse event was reported in 99.7 % of patients [33]. The most commonly reported adverse events were gastrointestinal and skin-related events, although these were generally mild to moderate in severity and rarely led to treatment withdrawal. Treatment-emergent adverse events occurring in C15 % of the integrated population included nausea (40 %), rash (26 %), dizziness, (23 %), dyspepsia (21 %) and vomiting (18 %). Of note, the inci- dence of new-onset gastrointestinal and skin-related adverse events declined after the first 6 months of treat- ment. Serious treatment-emergent adverse events occurred in 53 % of patients. The most commonly reported serious treatment-emergent adverse event was worsening IPF, which was consistent with prior studies and with the pro- gressive nature of the disease. Treatment was discontinued because of treatment-emergent adverse events in 35.1 % of patients. Increased AST or ALT levels [3 9 ULN were seen in 2.7 % of patients. The crude all-cause mortality and IPF-related mortality rates were 18.8 and 11.2 %, respec- tively. The adjusted incidence was six deaths per 100 person-exposure years for all-cause mortality and 4.3 deaths per 100 person-exposure years for IPF-related mortality [33].

A subsequent assessment of the patients from an interim data cut-off date of 14 May 2012 showed that pirfenidone was generally well tolerated for up to 8.6 years [46]. Consistent with the previous report, the most commonly reported adverse events were mild to moderate gastroin- testinal and skin-related events that rarely led to treatment withdrawal (data available as an abstract) [46].

5.3 Real-World Tolerability

The adverse event profile of pirfenidone in real-world studies appeared similar to that seen in clinical trials [38, 39, 41–44]. Adverse events reported most commonly in real-world studies included gastrointestinal adverse events [38, 39, 41–44] and skin-related adverse events [44], including photosensitivity reactions [39, 41, 44]. Gastro- intestinal adverse events were the most common reason for patients discontinuing treatment in two studies [38, 41].

According to an interim analysis of PASSPORT (Post- Authorization Safety Study of Esbriet® (pirfenidone): a Prospective Observational Registry to Evaluate Long-Term Safety in a Real-World Setting; study 025) [47, 48], no new safety issues emerged compared with results of clin- ical trials of pirfenidone in IPF patients (data available as an abstract) [47]. PASSPORT, a multinational prospective safety study required by the European Medicines Agency (EMA), was designed to collect adverse drug reaction information for up to 2 years from approximately 1,000 patients receiving pirfenidone for IPF or another disease [47, 48]. Based on an interim analysis of 530 patients, 58.7 % of patients developed at least one adverse drug reaction [47]. Reported adverse drug reac- tions included gastrointestinal events (30.4 %), photosen- sitivity/rash (19.1 %), fatigue (18.5 %) and weight loss (10.6 %). Serious adverse drug reactions were seen in
5.8 % of patients. There were less drug discontinuations when adverse drug reactions were managed with dose adjustments [47].

According to the EU SPC and the US prescribing information, reports of angioedema have been received in the post-marketing setting [11, 12]. A history of angioedema with pirfenidone is a contraindication to treatment with pirfenidone in the EU (Sect. 6). Increased bilirubin levels, in combination with increased ALT and AST levels, and agranulocytosis were rare adverse reactions also identified through post-marketing surveil- lance [11, 12].

6 Dosage and Administration

Pirfenidone is approved in the EU for the treatment of adults with mild to moderate IPF [11] and in the USA for the treatment of IPF [12]. Pirfenidone is supplied as 267 mg capsules [11, 12]. Pirfenidone therapy is initiated with a 14-day titration regimen of 801 mg/day (one cap- sule, three times daily) on days 1–7 and 1,602 mg/day (two capsules, three times daily) on days 8–14. The rec- ommended daily dosage from day 15 onwards is pirfeni- done 2,403 mg/day (three capsules, three times daily). Pirfenidone capsules should be taken with food [11, 12]. The EU SPC states that pirfenidone should be swallowed whole with water [11], and the US prescribing information states that doses should be taken at the same time each day [12]. In addition, patients should minimize or avoid exposure to direct sunlight during pirfenidone therapy [11, 12]. Patients are advised to apply sunblock daily, wear clothing that protects them from sun exposure and avoid taking other medications known to cause photosensitivity [11, 12].

Contraindications listed in the EU SPC include con- comitant therapy with fluvoxamine, severe hepatic impairment, severe renal impairment, end-stage liver dis- ease, end-stage renal disease requiring dialysis or a history of angioedema with pirfenidone [11]. In the US prescribing information, no contraindications are listed for pirfenidone therapy [12]. Local prescribing information should be consulted for further information, including contraindications, dosage adjustments in patients experiencing photosensitivity reactions, rash or gastrointestinal disorders, special warn- ings and precautions for use.

7 Place of Pirfenidone in the Management of Idiopathic Pulmonary Fibrosis

IPF is a debilitating disease that is associated with an irreversible decline in lung function until eventual death from either respiratory failure or a complicating comor- bidity [1, 49]. 2011 IPF treatment guidelines from the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS) and Latin American Thoracic Association (ALAT) strongly recommend lung transplantation in appropriate patients and long-term oxygen therapy in patients with clinically sig- nificant resting hypoxaemia, but do not support the use of any specific pharmacological agent in the treatment of IPF because of insufficient data [1]. Pirfenidone, anticoagulants and acetylcysteine, either as monotherapy or in combina- tion with both azathioprine and prednisone, are suggested as options for well-informed patients who strongly desire pharmacological therapy. Since the publication of the guidelines, which were based on evidence collected through May 2010, there have been several major devel- opments [1].

In February 2011, pirfenidone became the first drug to be approved in the EU for the treatment of adults with mild to moderate IPF [11, 50]. The EMA granted marketing authorization for pirfenidone in the EU based on the determination that pirfenidone had a favourable risk-ben- efit balance in the treatment of IPF [20]. Results from the CAPACITY trials (Sect. 4.1) were pivotal in this deter- mination [20].
In April 2011, the Anticoagulant Effectiveness in Idio- pathic Pulmonary Fibrosis (ACE-IPF) trial was terminated because of safety concerns [51]. ACE-IPF, which com- pared the efficacy of warfarin with that of placebo in patients with progressive IPF, was stopped prematurely because warfarin was associated with an increased risk of mortality. Investigators concluded that warfarin should not be used for the treatment of progressive IPF [51].

In October 2011, the three-drug regimen (prednisone, azathioprine and acetylcysteine) arm of PANTHER-IPF (Prednisone, Azathioprine, and N-acetylcysteine: a Study That Evaluates Response in Idiopathic Pulmonary Fibro- sis) was prematurely terminated because of safety con- cerns [52, 53]. In PANTHER-IPF, which was examining three treatment arms in patients with mild to moderate IPF, treatment with the three-drug regimen was associated with a significantly increased risk of hospitalizations, mortality and serious adverse events compared with pla- cebo [52, 53]. Therefore, a clinical alert was issued. The trial continued with two treatment groups (acetylcysteine vs. placebo), and final results led to the conclusion that acetylcysteine did not help preserve FVC in patients with mild to moderate IPF. Trends toward a favourable response were seen in the acetylcysteine group for a number of outcomes before the clinical alert, whereas trends toward a favourable response with placebo were seen after the clinical alert. An explanation was not evi- dent for these findings [52].

In May 2014, full results of the ASCEND trial were published that supported the efficacy of pirfenidone in the treatment of patients with mild to moderate IPF [28]. Although results with respect to the primary endpoint were mixed in the CAPACITY trials, pirfenidone met the pri- mary endpoint in ASCEND and was shown to significantly reduce the change in percentage predicted FVC from baseline to week 52 (Sect. 4.1). Despite the three-times- daily dosing schedule, treatment adherence was good ([85 %) in both CAPACITY and ASCEND (Sect. 4.1). In addition, pooled data from the CAPACITY and ASCEND trials showed that pirfenidone significantly reduced both IPF-related mortality and all-cause mortality compared with placebo (Sect. 4.1). There is a need for longer-term efficacy data, and results from the RECAP extension of CAPACITY/ASCEND are anticipated.

Also in May 2014, full results of two identical phase III trials (INPULSIS-1 and INPULSIS-2) were published that supported the efficacy of nintedanib (BIBF 1120) in the treatment of IPF [54]. Nintedanib, an intracellular inhibitor targeting multiple tyrosine kinases, significantly reduced the rate of FVC decline in both trials compared with pla- cebo. However, a prespecified pooled analysis across both trials did not show a significant between-group difference in terms of all-cause and respiratory-cause mortality. In addition, the effect of nintedanib on time to first acute exacerbation and change from baseline in total score on the St. George’s Respiratory Questionnaire was inconsistent between INPULSIS-1 and INPULSIS-2. The most fre- quently reported adverse events were gastrointestinal in nature, with the majority of nintedanib recipients experi- encing diarrhoea in both studies [54].

In October 2014, the US FDA approved both pirfeni- done (Esbriet®) and nintedanib (Ofev®) for the treatment of IPF [55]. They are the first two FDA-approved drugs available for IPF patients in the USA [13]. A study comparing the efficacy and safety of nintedanib and pirfenidone would be of interest.

Results of real-world studies in patients with IPF receiving pirfenidone appeared consistent with those obtained in the CAPACITY and ASCEND trials (Sect. 4.2). Although the adherence rates in real-world studies was numerically lower than that of clinical trials (Sect. 4.2), results of a real-world study suggest that pirfenidone adherence rates can be improved and optimized by implementing regular specialist nurse reviews [42].

Long-term safety and tolerability studies such as RECAP and PASSPORT are ongoing, but interim analyses supported the tolerability profile of pirfenidone seen in the CAPACITY and ASCEND trials (Sects. 5.2 and 5.3). The most common treatment-emergent adverse events were gastrointestinal and skin-related events that were generally mild to moderate in severity. Gastrointestinal adverse events can be reduced by taking pirfenidone with or after a meal, and skin-related adverse events can be better man- aged by avoiding sun exposure, applying broad-spectrum sunscreen and wearing protective clothing [49]. Monitoring of liver function tests is recommended in pirfenidone recipients (Sect. 3.3), although elevated transaminase lev- els were not accompanied by clinically significant sequelae in the CAPACITY and ASCEND trials (Sect. 5.1).

In light of recent developments, several European countries have updated their national IPF guidelines to recommend pirfenidone for the first-line treatment of patients with mild to moderate IPF [50, 56–58]. Although lung transplantation has been shown to improve survival, most IPF patients are not eligible for the procedure because of old age, severe limitations in functional status or comorbidities [50]. Among the pharmacological options for IPF in the current ATS/ERS/JRS/ALAT guidelines, pirfenidone is the only drug that has demonstrated rea- sonable efficacy and tolerability.

Although pirfenidone is costly and results of cost- effectiveness analyses are mixed [56, 59, 60], it is reim- bursed in several countries [61–63]. Country-specific analyses of cost effectiveness would be of interest. In addition, the results of PANORAMA (A randomized, double-blind, placebo-controlled, phase 2 study of the safety and tolerability of N-acetylcysteine in patients with idiopathic pulmonary fibrosis with background treatment of pirfenidone) [64] are anticipated to determine the safety of pirfenidone in combination therapy. Data from a phase II trial (NCT01933334) examining pirfenidone in patients with systemic sclerosis-related interstitial lung disease are also awaited with interest to determine the possible use of pirfenidone in other indications [35].

In conclusion, oral pirfenidone is an effective and gen- erally well-tolerated drug for IPF. The use of pirfenidone in patients with mild to moderate IPF slows the rate of decline in FVC and improves survival. Pirfenidone may also reduce the decline in 6MWT distances. Thus, pirfenidone is a valuable new agent for patients with IPF.

Disclosure The preparation of this review was not supported by any external funding. Esther S. Kim and Gillian M. Keating are salaried employees of Adis/Springer. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the authors on the basis of scientific and editorial merit.

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