Pirfenidone 600 mg · Tablets

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

Absorption — After single oral-dose administration of 801 mg pirfenidone (three 267 mg capsules), the maximum observed plasma concentration (C max) was achieved between 30 minutes and 4 hours (median time of 0.5 hours). Food decreased the rate and extent of absorption. Median T maxincreased from 0.5 hours to 3 hours with food. Maximum plasma concentrations (C max) and AUC 0-infdecreased 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 mcg/mL). Mean apparent oral volume of distribution is approximately 59 to 71 liters.

Metabolism — In vitroprofiling 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 vitrodata 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).

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, AUC 0-infand C maxof 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 (CL cr50 to 80 mL/min), moderate (CL cr30 to 50 mL/min), and severe (CL crless than 30 mL/min) renal impairment (n=6/group) and in 6 subjects with normal CL cr(greater than or equal to 80 mL/min) renal function. Results showed that systemic exposure (AUC 0-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 AUC 0-infof 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/m 2) 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.