Pharmacokinetics, Safety and Tolerability of Pirfenidone and its Major Metabolite after Single and Multiple Oral Doses in Healthy Chinese Subjects under Fed Conditions

Abstract

Background and objective:

Pirfenidone is a promising antifibrotic agent with therapeutic potential for idiopathic pulmonary fibrosis. This study aimed to evaluate the pharmacokinetics and urinary excretion of pirfenidone and its major metabolite 5-carboxy-pirfenidone in healthy Chinese subjects under fed conditions.

Methods:

20 healthy subjects of either sex were recruited in this randomized, single-center, and open-label, single ascending doses (200, 400, and 600 mg) and multiple doses (400 mg, 3 times daily) study. Safety was assessed by adverse events, ECGs, vital signs, and clinical laboratory parameters. Blood and urine samples were analyzed with a validated LC/MS method.

Results and conclusion:

Pirfenidone was safe and well tolerated. After single-dose administration, pirfenidone was rapidly absorbed with a mean T_max of 1.8–2.2 h and a mean t_1/2 of 2.1–2.4 h. 5-carboxy-pirfenidone was rapidly formed with a mean T_max of 1.5–2.2 h and a mean t_1/2 of 2.1–2.6 h. C_max and AUC for both parent and metabolite were dose proportional over the 200–600 mg dose range. No gender effect was found. In the steady state, the accumulation index (R) estimated for the 3 dosing intervals ranged from 1.1 to 1.5 for both pirfenidone and 5-carboxy-pirfenidone, indicating that the exposure of pirfenidone and 5-carboxy-pirfenidone increased slightly with repeated dosing, but t_1/2 and CL/F remained unchanged. Metabolism is the primary mechanism of drug clearance of pirfenidone. About 87.76% of the administered pirfenidone was excreted in urine in the form of 5-carboxy-pirfenidone, while only 0.6159% of the administered pirfenidone was detected as the unchanged form in urine.

Key words

pirfenidone - metabolite - 5-carboxy-pirfenidone - pharmacokinetics

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