Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639, Grenzach-Wyhlen, Germany
Pharmacotherapeutic group: Immunosuppressants, other immunosuppressants
ATC code: L04AX05
The mechanism of action of pirfenidone has not been fully established. However, existing data suggest that pirfenidone exerts both antifibrotic and anti-inflammatory properties in a variety of in vitro systems and animal models of pulmonary fibrosis (bleomycin- and transplant-induced fibrosis).
IPF is a chronic fibrotic and inflammatory pulmonary disease affected by the synthesis and release of pro-inflammatory cytokines including tumour necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1β) and pirfenidone has been shown to reduce the accumulation of inflammatory cells in response to various stimuli.
Pirfenidone attenuates fibroblast proliferation, production of fibrosis-associated proteins and cytokines, and the increased biosynthesis and accumulation of extracellular matrix in response to cytokine growth factors such as, transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF).
The clinical efficacy of Esbriet has been studied in four Phase 3, multicentre, randomised, double-blind, placebo-controlled studies in patients with IPF. Three of the Phase 3 studies (PIPF-004, PIPF-006, and PIPF-016) were multinational, and one (SP3) was conducted in Japan.
PIPF-004 and PIPF-006 compared treatment with Esbriet 2403 mg/day to placebo. The studies were nearly identical in design, with few exceptions including an intermediate dose group (1,197 mg/day) in PIPF-004. In both studies, treatment was administered three times daily for a minimum of 72 weeks. The primary endpoint in both studies was the change from Baseline to Week 72 in percent predicted Forced Vital Capacity (FVC).
In study PIPF-004, the decline of percent predicted FVC from Baseline at Week 72 of treatment was significantly reduced in patients receiving Esbriet (N=174) compared with patients receiving placebo (N=174; p=0.001, rank ANCOVA). Treatment with Esbriet also significantly reduced the decline of percent predicted FVC from Baseline at Weeks 24 (p=0.014), 36 (p<0.001), 48 (p<0.001), and 60 (p<0.001). At Week 72, a decline from baseline in percent predicted FVC of ≥10% (a threshold indicative of the risk of mortality in IPF) was seen in 20% of patients receiving Esbriet compared to 35% receiving placebo (Table 2).
Table 2. Categorical assessment of change from Baseline to Week 72 in percent predicted FVC in study PIPF-004:
| Pirfenidone 2,403 mg/ημέρα (N=174) | Placebo (N=174) | |
|---|---|---|
| Decline of ≥10% or death or lung transplant | 35 (20%) | 60 (34%) |
| Decline of less than 10% | 97 (56%) | 90 (52%) |
| No decline (FVC change >0%) | 42 (24%) | 24 (14%) |
Although there was no difference between patients receiving Esbriet compared to placebo in change from Baseline to Week 72 of distance walked during a six minute walk test (6MWT) by the prespecified rank ANCOVA, in an ad hoc analysis, 37% of patients receiving Esbriet showed a decline of ≥50 m in 6MWT distance, compared to 47% of patients receiving placebo in PIPF-004.
In study PIPF-006, treatment with Esbriet (N=171) did not reduce the decline of percent predicted FVC from Baseline at Week 72 compared with placebo (N=173; p=0.501). However, treatment with Esbriet reduced the decline of percent predicted FVC from Baseline at Weeks 24 (p<0.001), 36 (p=0.011), and 48 (p=0.005). At Week 72, a decline in FVC of ≥10% was seen in 23% of patients receiving Esbriet and 27% receiving placebo (Table 3).
Table 3. Categorical assessment of change from Baseline to Week 72 in percent predicted FVC in study PIPF-006:
| Pirfenidone 2,403 mg/day (N=171) | Placebo (N=173) | |
|---|---|---|
| Decline of ≥10% or death or lung transplant | 39 (23%) | 46 (27%) |
| Decline of less than 10% | 88 (52%) | 89 (51%) |
| No decline (FVC change >0%) | 44 (26%) | 38 (22%) |
The decline in 6MWT distance from Baseline to Week 72 was significantly reduced compared with placebo in study PIPF-006 (p<0.001, rank ANCOVA). Additionally, in an ad hoc analysis, 33% of patients receiving Esbriet showed a decline of ≥50 m in 6MWT distance, compared to 47% of patients receiving placebo in PIPF-006.
In a pooled analysis of survival in PIPF-004 and PIPF-006 the mortality rate with Esbriet 2403 mg/day group was 7.8% compared with 9.8% with placebo (HR 0.77 [95% CI, 0.47–1.28]).
PIPF-016 compared treatment with Esbriet 2,403 mg/day to placebo. Treatment was administered three times daily for 52 weeks. The primary endpoint was the change from Baseline to Week 52 in percent predicted FVC. In a total of 555 patients, the median baseline percent predicted FVC and DLCO were 68 (range: 48–91%) and 42% (range: 27–170%), respectively. Two percent of patients had percent predicted FVC below 50% and 21% of patients had a percent predicted DLCO below 35% at Baseline.
In study PIPF-016, the decline of percent predicted FVC from Baseline at Week 52 of treatment was significantly reduced in patients receiving Esbriet (N=278) compared with patients receiving placebo (N=277; p<0.000001, rank ANCOVA). Treatment with Esbriet also significantly reduced the decline of percent predicted FVC from Baseline at Weeks 13 (p<0.000001), 26 (p<0.000001), and 39 (p=0.000002). At Week 52, a decline from Baseline in percent predicted FVC of ≥10% or death was seen in 17% of patients receiving Esbriet compared to 32% receiving placebo (Table 4).
Table 4. Categorical assessment of change from Baseline to Week 52 in percent predicted FVC in study PIPF-016:
| Pirfenidone 2,403 mg/day (N=278) | Placebo (N=277) | |
|---|---|---|
| Decline ≥10% or death | 46 (17%) | 88 (32%) |
| Decline of less than 10% | 169 (61%) | 162 (58%) |
| No decline (FVC change >0%) | 63 (23%) | 27 (10%) |
The decline in distance walked during a 6MWT from Baseline to Week 52 was significantly reduced in patients receiving Esbriet compared with patients receiving placebo in PIPF-016 (p=0.036, rank ANCOVA); 26% of patients receiving Esbriet showed a decline of ≥50 m in 6MWT distance compared to 36% of patients receiving placebo.
In a pre-specified pooled analysis of studies PIPF-016, PIPF-004, and PIPF-006 at Month 12, all-cause mortality was significantly lower in Esbriet 2403 mg/day group (3.5%, 22 of 623 patients) compared with placebo (6.7%, 42 of 624 patients), resulting in a 48% reduction in the risk of all-cause mortality within the first 12 months (HR 0.52 [95% CI, 0.31–0.87], p=0.0107, log-rank test).
The study (SP3) in Japanese patients compared pirfenidone 1800 mg/day (comparable to 2403 mg/day in the US and European populations of PIPF-004/006 on a weight-normalised basis) with placebo (N=110, N=109, respectively). Treatment with pirfenidone significantly reduced mean decline in vital capacity (VC) at Week 52 (the primary endpoint) compared with placebo (-0.09±0.02 l versus -0.16±0.02 l respectively, p=0.042).
The European Medicines Agency has waived the obligation to submit the results of studies with Esbriet in all subsets of the paediatric population in IPF (see section 4.2 for information on paediatric use).
Administration of Esbriet capsules with food results in a large reduction in Cmax (by 50%) and a smaller effect on AUC, compared to the fasted state. Following oral administration of a single dose of 801 mg to healthy older adult volunteers (50-66 years of age) in the fed state, the rate of pirfenidone absorption slowed, while the AUC in the fed state was approximately 80-85% of the AUC observed in the fasted state. Bioequivalence was demonstrated in the fasted state when comparing the 801 mg tablet to three 267 mg capsules. In the fed state, the 801 mg tablet met bioequivalence criteria based on the AUC measurements compared to the capsules, while the 90% confidence intervals for Cmax (108.26%-125.60%) slightly exceeded the upper bound of standard bioequivalence limit (90% CI: 80.00%-125.00%). The effect of food on pirfenidone oral AUC was consistent between the tablet and capsule formulations. Compared to the fasted state, administration of either formulation with food reduced pirfenidone Cmax, with Esbriet tablet reducing the Cmax slightly less (by 40%) than Esbriet capsules (by 50%). A reduced incidence of adverse events (nausea and dizziness) was observed in fed subjects when compared to the fasted group. Therefore, it is recommended that Esbriet be administered with food to reduce the incidence of nausea and dizziness.
The absolute bioavailability of pirfenidone has not been determined in humans.
Pirfenidone binds to human plasma proteins, primarily to serum albumin. The overall mean binding ranged from 50% to 58% at concentrations observed in clinical studies (1 to 100 μg/ml). Mean apparent oral steady-state volume of distribution is approximately 70 l, indicating that pirfenidone distribution to tissues is modest.
Approximately 70–80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6, and 2E1. In vitro data indicate some pharmacologically relevant activity of the major metabolite (5-carboxy-pirfenidone) at concentrations in excess of peak plasma concentrations in IPF patients. This may become clinically relevant in patients with moderate renal impairment where plasma exposure to 5-carboxy-pirfenidone is increased.
The oral clearance of pirfenidone appears modestly saturable. In a multiple-dose, dose-ranging study in healthy older adults administered doses ranging from 267 mg to 1,335 mg three times a day, the mean clearance decreased by approximately 25% above a dose of 801 mg three times a day. Following single dose administration of pirfenidone in healthy older adults, the mean apparent terminal elimination half-life was approximately 2.4 hours. Approximately 80% of an orally administered dose of pirfenidone is cleared in the urine within 24 hours of dosing. The majority of pirfenidone is excreted as the 5-carboxy-pirfenidone metabolite (>95% of that recovered), with less than 1% of pirfenidone excreted unchanged in urine.
The pharmacokinetics of pirfenidone and the 5-carboxy-pirfenidone metabolite were compared in subjects with moderate hepatic impairment (Child-Pugh Class B) and in subjects with normal hepatic function. Results showed that there was a mean increase of 60% in pirfenidone exposure after a single dose of 801 mg pirfenidone (3 × 267 mg capsule) in patients with moderate hepatic impairment. Pirfenidone should be used with caution in patients with mild to moderate hepatic impairment and patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor (see sections 4.2 and 4.4). Esbriet is contraindicated in severe hepatic impairment and end stage liver disease (see sections 4.2 and 4.3).
No clinically relevant differences in the pharmacokinetics of pirfenidone were observed in subjects with mild to severe renal impairment compared with subjects with normal renal function. The parent substance is predominantly metabolised to 5-carboxy-pirfenidone. The mean (SD) AUC0-∞ of 5-carboxy-pirfenidone was significantly higher in the moderate (p=0.009) and severe (p<0.0001) renal impairment groups than in the group with normal renal function; 100 (26.3) mg•h/L and 168 (67.4) mg•h/L compared to 28.7 (4.99) mg•h/L respectively.
| Renal Impairment Group | Statistics | AUC0-∞ (mg•hr/L) | |
|---|---|---|---|
| Pirfenidone | 5-Carboxy-Pirfenidone | ||
| Normal n=6 | Mean (SD) | 42.6 (17.9) | 28.7 (4.99) |
| Median (25th–75th) | 42.0 (33.1–55.6) | 30.8 (24.1–32.1) | |
| Mild n=6 | Mean (SD) | 59.1 (21.5) | 49.3a (14.6) |
| Median (25th–75th) | 51.6 (43.7–80.3) | 43.0 (38.8–56.8) | |
| Moderate n=6 | Mean (SD) | 63.5 (19.5) | 100b (26.3) |
| Median (25th–75th) | 66.7 (47.7–76.7) | 96.3 (75.2–123) | |
| Severe n=6 | Mean (SD) | 46.7 (10.9) | 168c (67.4) |
| Median (25th–75th) | 49.4 (40.7–55.8) | 150 (123–248) | |
AUC0-∞ =area under the concentration-time curve from time zero to infinity.
a p-value versus Normal = 1.00 (pair-wise comparison with Bonferroni)
b p-value versus Normal = 0.009 (pair-wise comparison with Bonferroni)
c p-value versus Normal < 0.0001 (pair-wise comparison with Bonferroni)
Exposure to 5-carboxy-pirfenidone increases 3.5 fold or more in patients with moderate renal impairment. Clinically relevant pharmacodynamic activity of the metabolite in patients with moderate renal impairment cannot be excluded. No dose adjustment is required in patients with mild renal impairment who are receiving pirfenidone. Pirfenidone should be used with caution in patients with moderate renal impairment. The use of pirfenidone is contraindicated in patients with severe renal impairment (CrCl <30ml/min) or end stage renal disease requiring dialysis (see sections 4.2 and 4.3).
Population pharmacokinetic analyses from 4 studies in healthy subjects or subjects with renal impairment and one study in patients with IPF showed no clinically relevant effect of age, gender or body size on the pharmacokinetics of pirfenidone.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
In repeated dose toxicity studies increases in liver weight were observed in mice, rats and dogs; this was often accompanied by hepatic centrilobular hypertrophy. Reversibility was observed after cessation of treatment. An increased incidence of liver tumours was observed in carcinogenicity studies conducted in rats and mice. These hepatic findings are consistent with an induction of hepatic microsomal enzymes, an effect which has not been observed in patients receiving Esbriet. These findings are not considered relevant to humans.
A statistically significant increase in uterine tumours was observed in female rats administered 1,500 mg/kg/day, 37 times the human dose of 2,403 mg/day. The results of mechanistic studies indicate that the occurrence of uterine tumours is probably related to a chronic dopamine-mediated sex hormone imbalance involving a species specific endocrine mechanism in the rat which is not present in humans.
Reproductive toxicology studies demonstrated no adverse effects on male and female fertility or postnatal development of offspring in rats and there was no evidence of teratogenicity in rats (1,000 mg/kg/day) or rabbits (300 mg/kg/day). In animals placental transfer of pirfenidone and/or its metabolites occurs with the potential for accumulation of pirfenidone and/or its metabolites in amniotic fluid. At high doses (≥450 mg/kg/day) rats exhibited a prolongation of oestrous cycle and a high incidence of irregular cycles. At high doses (≥1,000 mg/kg/day) rats exhibited a prolongation of gestation and reduction in fetal viability. Studies in lactating rats indicate that pirfenidone and/or its metabolites are excreted in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk.
Pirfenidone showed no indication of mutagenic or genotoxic activity in a standard battery of tests and when tested under UV exposure was not mutagenic. When tested under UV exposure pirfenidone was positive in a photoclastogenic assay in Chinese hamster lung cells.
Phototoxicity and irritation were noted in guinea pigs after oral administration of pirfenidone and with exposure to UVA/UVB light. The severity of phototoxic lesions was minimised by application of sunscreen.
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