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

Pirfenidone was safe and well tolerated. After single-dose administration, pirfenidone was rapidly absorbed with a mean Tmax of 1.8-2.2 h and a mean t1/2 of 2.1-2.4 h. 5-carboxy-pirfenidone was rapidly formed with a mean Tmax of 1.5-2.2 h and a mean t1/2 of 2.1-2.6 h. Cmax 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 t1/2 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.