Pirfenidone (Page 4 of 7)

10 OVERDOSAGE

There is limited clinical experience with overdosage. Multiple dosages of pirfenidone up to a maximum tolerated dose of 4,005 mg per day were administered as five 267 mg doses three times daily to healthy adult volunteers over a 12-day dose escalation.

In the event of a suspected overdosage, appropriate supportive medical care should be provided, including monitoring of vital signs and observation of the clinical status of the patient.

11 DESCRIPTION

Pirfenidone belongs to the chemical class of pyridone. Pirfenidone tablets are available for oral administration as film-coated tablets containing 267 mg (yellow) and 801 mg (purple) pirfenidone.

Pirfenidone has a molecular formula of C12 H11 NO and a molecular weight of 185.23. Pirfenidone has the following structural formula, which has been referred to as 5-methyl-1-phenyl-2-1(H)-pyridone or 5-methyl-1-phenyl-2-(1H)-pyridone.

formula

Pirfenidone is a white to pale yellow, non-hygroscopic powder. It is more soluble in methanol, ethyl alcohol, acetone and chloroform than in water and 1.0 N HCl. The melting point is approximately 109°C.

Pirfenidone tablets contain pirfenidone and the following inactive ingredients: black iron oxide, colloidal silicon dioxide, croscarmellose sodium, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, talc, and titanium dioxide. In addition, the 801 mg strength contains iron oxide red.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of pirfenidone in the treatment of IPF has not been established.

12.2 Pharmacodynamics

Cardiac Electrophysiology:

The effect of pirfenidone on QT interval was evaluated in a randomized, placebo, and positive controlled parallel study in 160 healthy adult volunteers. Volunteers received pirfenidone 2,403 mg/day (recommended dose) and 4,005 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 pirfenidone 2,403 mg/day and 4,005 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 pirfenidone 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 pirfenidone at 4,005 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.

12.3 Pharmacokinetics

Absorption:

After single oral-dose administration of 801 mg pirfenidone, the maximum observed plasma concentration (Cmax ) was achieved between 30 minutes and 4 hours (median time of 0.5 hours). Food decreased 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.

Bioequivalence was demonstrated in the fasted state when comparing the 801 mg tablet to three 267 mg capsules. The effect of food on pirfenidone exposure was consistent between the tablet and capsule formulations.

A reduced incidence of adverse reactions was observed in the fed group when compared to the fasted group. In controlled studies with IPF patients, pirfenidone was taken with food [see Dosage and Administration (2) and Clinical Studies (14)].

The absolute bioavailability of pirfenidone has not been determined in humans.

Distribution:

Pirfenidone 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 pirfenidone is primarily metabolized in the liver by CYP1A2 and multiple other CYPs (CYP2C9, 2C19, 2D6, and 2E1). Oral administration of pirfenidone results in the formation of four metabolites. In humans, only pirfenidone and 5-carboxy-pirfenidone are present in plasma in significant quantities. The mean 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.

Elimination:

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 pirfenidone was excreted as the 5-carboxy metabolite (approximately 99.6% of that recovered).

Specific Populations:

Hepatic Impairment

The pharmacokinetics of pirfenidone and the 5-carboxy-pirfenidone metabolite were 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 and Cmax 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

The pharmacokinetics of pirfenidone and the 5-carboxy-pirfenidone metabolite were studied in 18 subjects with mild (CLcr 50 to 80 mL/min), moderate (CLcr 30 to 50 mL/min), and severe (CLcr less than 30 mL/min) renal impairment (n=6/group) and in 6 subjects with normal CLcr (greater than or equal to 80 mL/min) renal function. Results showed that systemic exposure (AUC0-inf ) to pirfenidone increased approximately 1.4, 1.5, and 1.2-fold in subjects with mild, moderate and severe renal impairment, respectively. The corresponding AUC0-inf of 5-carboxy-pirfenidone increased 1.7, 3.4, and 5.6-fold, although the change in the patients with mild renal impairment was not statistically significant. The renal clearance of 5-carboxy-pirfenidone decreased significantly in patients with moderate to severe renal impairment.

The pharmacokinetics and safety of pirfenidone has not been studied in subjects with end- stage renal disease requiring dialysis.

Geriatric

Results of population pharmacokinetic analysis suggest that no dosage adjustment is needed in geriatric patients.

Gender

Results of population pharmacokinetic analysis of pirfenidone 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 pirfenidone.

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, pirfenidone 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 pirfenidone and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) on Day 6 (ciprofloxacin was dosed at 750 mg twice daily from Day 2 to Day 7) increased the exposure to pirfenidone by 81%.

Cytochrome P450 1A2 Inducers

Following a single oral dose of 801 mg pirfenidone in 25 smokers and 25 healthy nonsmokers, the systemic exposure in smokers was significantly lower compared to nonsmokers. AUC0-inf and Cmax 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 1,000 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 1,000 µM (approximately 10-fold the mean human Cmax ). Pirfenidone showed a concentration-dependent inhibition on CYP2C9, 2C19 or 1A2, 2D6, and 3A4. At 1,000 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.

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