Pharmacology: Mechanism of Action:
The mechanism of action of pirfenidone in the treatment of IPF has not been established.
Pharmacodynamics: Cardiac Electrophysiology:
The effect of ESBRIET on QT interval was evaluated in a randomized, placebo, and positive controlled parallel study in 160 healthy adult volunteers. Volunteers received ESBRIET 2403 mg/day (recommended dosage) and 4005 mg/day (1.6 times recommended dose) or placebo for 10 days or a single dose of 400 mg moxifloxacin (active control).
Relative to placebo, the maximum mean change from baseline in study-specific QT interval was 3.2 milliseconds (ms) and 2.2 ms for ESBRIET 2403 mg/day and 4005 mg/day, respectively. No volunteer had a QTc interval greater than 480 ms or change from baseline greater than 60 ms. Although there was no evidence that ESBRIET prolonged the QTc interval in this study, a definitive conclusion may not be drawn as the positive control (moxifloxacin) did not perform as expected in this study, and ESBRIET at 4005 mg/day (1.7 times the maximum recommended dose) did not cover the maximum pirfenidone exposure increase with co-administration of fluvoxamine, a strong CYP1A2 inhibitor.
The clinical efficacy of Esbriet has been studied in three multinational, Phase 3, multicenter, randomized, 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 (1197 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 in 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 in 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 (see Table 1).
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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 in percent predicted FVC from Baseline at Week 72 compared with placebo (N = 173; p = 0.501). However, treatment with Esbriet reduced the decline in 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 (see Table 2).
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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 2403 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 in 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 in 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 (see Table 3).
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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).
After single oral-dose administration of 801 mg ESBRIET (three 267 mg capsules), the maximum observed plasma concentration (Cmax
) was achieved between 30 minutes and 4 hours (median time of 0.5 hours). Food decrease the rate and extent of absorption. Median Tmax
increased from 0.5 hours to 3 hours with food. Maximum plasma concentrations (Cmax
) and AUC0-inf
decreased by approximately 49% and 16% with food, respectively. A reduced incidence of adverse reactions was observed in the fed group when compared to the fasted group. In controlled studies with IPF patients, ESBRIET was taken with food (see Dosage & Administration and Clinical Efficacy previously mentioned).
The absolute bioavailability of pirfenidone has not been determined in humans.
ESBRIET binds to human plasma proteins, primarily to serum albumin, in a concentration-independent manner over the range of concentrations observed in clinical trials. The overall mean binding was 58% at concentrations observed in clinical studies (1 to 10 μg/mL). Mean apparent oral volume of distribution is approximately 59 to 71 liters.
Metabolism: In vitro
profiling studies in hepatocytes and liver microsomes have shown that ESBRIET is primarily metabolized in the liver by CYP1A2 and multiple other CYPs (CYP2C9, 2C19, 2D6, and 2E1). Oral administration of ESBRIET results in the formation of four metabolites. In humans, only pirfenidone and 5-carboxy-pirfenidone are present in plasma in significant quantities. Themean metabolite-to-parent ratio ranged from approximately 0.6 to 0.7.
No formal radiolabeled studies have assessed the metabolism of pirfenidone in humans. In vitro
data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.
The mean terminal half-life is approximately 3 hours in healthy subjects. Pirfenidone is excreted predominantly as metabolite 5-carboxy-pirfenidone, mainly in the urine (approximately 80% of the dose). The majority of ESBRIET was excreted as the 5-carboxy metabolite (approximately 99.6% of that recovered).
Hepatic Impairment: The pharmacokinetics of ESBRIET and the 5-carboxy-pirfenidonemetabolitewere studied in 12 subjects with moderate hepatic impairment (Child Pugh Class B) and in 12 subjects with normal hepatic function. Results showed that the mean exposure, AUC0-inf
of pirfenidone increased approximately 1.6- and approximately 1.4-fold in subjects with moderate hepatic impairment, respectively. The exposure of 5-carboxy-pirfenidone did not change significantly in subjects with moderate hepatic impairment.
Renal Impairment: 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 drug is predominantly metabolized to 5-carboxy-pirfenidone, for which pharmacodynamics and safety margins were not established. The 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. The predicted amount of metabolite accumulation at steady state is not pharmacodynamically important because the terminal elimination half-life is only 1-2 hours in these subjects and there is no or minimal pharmacologic activity of the metabolite as measured by TNF inhibitory effects.
The pharmacokinetics and safety of ESBRIET has not been studied in patients with end-stage renal disease requiring dialysis and is not recommended in these patients.
Geriatric: Results of population pharmacokinetic analysis suggest that no dosage adjustment is needed in geriatric patients.
Gender: Results of population pharmacokinetic analysis of ESBRIET showed no significant differences in pharmacokinetics between males and females.
Obesity: Results of population pharmacokinetic analysis showed that obesity (Body Mass Index [BMI] greater than or equal to 30 kg/m2
) has no significant effect on the pharmacokinetics of ESBRIET.
Race: Population pharmacokinetic analysis showed that race has no significant effect on the pharmacokinetics of pirfenidone.
Drug Interaction Studies:
Cytochrome P450 1A2 Inhibitors: Pirfenidone is a substrate of cytochrome P450 1A2. In a single-dose drug interaction study in 25 healthy nonsmokers and 25 smokers, ESBRIET was coadministered with fluvoxamine (50 mg at bedtime for 3 days; 50 mg twice a day for 3 days, and 50 mg in the morning and 100 mg at bedtime for 4 days). An approximately 4-fold increase in exposure to pirfenidone in nonsmokers and approximately 7-fold increase in exposure in smokers was observed.
In a single-dose drug interaction study in 27 healthy subjects, coadministration of 801 mg of ESBRIET and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) on Day 6 (ciprofloxacin was dosed at 750 mg twice daily fromDay 2 to Day 7) increased the exposure to pirfenidone by 81%.
Cytochrome P450 1A2 Inducers: Following a single oral dose of 801 mg ESBRIET in 25 smokers and 25 healthy nonsmokers, the systemic exposure in smokers was significantly lower compared to nonsmokers. AUC0-inf
of pirfenidone in smokers were 46% and 68% of those in nonsmokers, respectively.
Inhibitory Effect of Pirfenidone on P-glycoprotein (Pgp): The potential for pirfenidone to inhibit Pgp mediated transport of digoxin (5.0 μM) was evaluated in the absence and presence of pirfenidone at concentrations ranging from 1 to 1000 μM in in vitro
system. Pirfenidone showed weak inhibition (10 to 30%) of Pgp facilitated digoxin B-A efflux at concentrations of 100 μM and above. Effect of pirfenidone upon Pgp substrate pharmacokinetics and safety has not been evaluated in humans.
Inhibitory Effect of Pirfenidone on CYP2C9, 2C19 or 1A2, 2D6, 3A4: The potential for pirfenidone to inhibit CYP2C9, 2C19 or 1A2 was evaluated in vitro
at concentrations up to 1000 μM (approximately 10-fold the mean human Cmax
). Pirfenidone showed a concentration-dependent inhibition on CYP2C9, 2C19 or 1A2, 2D6, and 3A4. At 1000 μM, pirfenidone inhibits the activity of these enzymes by 30.4%, 27.5%, 34.1%, 21%, and 9.6%, respectively. Effect of pirfenidone upon pharmacokinetics and safety of CYP2C9, 2C19, 1A2, 2D6, and 3A4 substrates has not been evaluated in humans.
Toxicology: Nonclinical Toxicology:
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Long-termstudies were conducted inmice and ratswith admixture of pirfenidone to the diet to evaluate its carcinogenic potential.
In a 24-month carcinogenicity study in B6C3F1 mice, pirfenidone caused statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma and hepatoblastoma in male mice at doses of 800 mg/kg and above (AUC exposure approximately 0.4 times adult exposure at the MRDD). There were statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma in female mice at doses of 2000 mg/kg and above (AUC exposure approximately 0.7 times adult exposure at the MRDD).
In a 24-month carcinogenicity study in Fischer rats, pirfenidone caused statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma in male rats at doses of 750 mg/kg and above (AUC exposure approximately 1.9 times adult exposure at the MRDD). There were statistically significant increases of the combination of hepatocellular adenoma and carcinoma and the combination of uterine adenocarcinoma and adenoma at a dose of 1500 mg/kg/day (AUC exposure approximately 3.0 times adult exposure at the MRDD).
The relevance of these tumor findings in rodents to humans is unknown.
Mutagenesis: Pirfenidone was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacteria, a chromosomal aberration test in Chinese hamster lung cells, and a micronucleus test in mice.
Impairment of Fertility: Pirfenidone had no effects on fertility and reproductive performance in rats at dosages up to 1000 mg/kg/day (approximately 3 times the MRDD in adults on a mg/m2