title: Pharmacokinetics, safety and tolerability of pirfenidone and its major metabolite after single and multiple oral doses in healthy Chinese subjects under fed conditions.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China.
authors.forename: N-Y
authors.initials: NY
authors.lastname: Huang
authors.forename: L
authors.initials: L
authors.lastname: Ding
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: Q-Y
authors.initials: QY
authors.lastname: Zhang
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.forename: H-D
authors.initials: HD
authors.lastname: Lin
authors.forename: W-Y
authors.initials: WY
authors.lastname: Hua
mesh_terms: D000284:Administration, Oral; D000328:Adult; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D011728:Pyridones; C093844:pirfenidone