Pirfenidone (Esbriet)

Indications

Idiopathic Pulmonary Fibrosis (IPF) (see Idiopathic Pulmonary Fibrosis, [[Idiopathic Pulmonary Fibrosis]])

  • FDA-Approved for this Indication in 10/14

Studies

  • CAPACITY 004 and 006 Trials (2011) [MEDLINE]
    • Main Findings: pirfenidone reduced the decline in FVC
    • Adverse Effects
      • Gastrointestinal Adverse Effects: nausea/vomiting, dyspepsia, anorexia
      • Other Adverse Effects: photosensitivity, rash, dizziness
  • ASCEND Trial (2014) [MEDLINE]
    • Trial: randomized, multi-center, placebo-controlled phase 3 trial (n = 555), 52 week duration, pirfenidone dose: 2403 mg qday
    • Main Findings
      • 47.9% decrease in patients who had at least a 10% decline in FVC or who died
      • 132.5% increase in patients with no decline in FVC
      • Improvement in progression-free survival
      • No change in all-cause mortality, death from IPF, or dyspnea scores
        • In pooled analysis with data from prior trials: decreased all-cause mortality and death from IPF
      • Decreased decline in 6-minute walk distance
    • Adverse Effects
      • Gastrointestinal Adverse Effects: elevated LFT’s, nausea/vomiting, anorexia, weight loss, GERD, dyspepsia
      • Dermatologic Adverse Effects: rash
      • Other Adverse Effects: insomnia

Pharmacology

  • Decrease in Fibroblast Proliferation and Synthesis of Fibrosis-Associated Proteins/Cytokines
  • Decrease in Transforming Growth Factor-Beta (TGF-Beta)-Induced Formation of Extracellular Matrix (Collagen)
  • Blocks Platelet-Derived Growth Factor-Induced Proliferative Effects

Metabolism

  • Hepatic: predominantly via CYP1A2 (to a lesser extent via CYP2C9, CYP2C19, CYP2D6, and CYP2E1)
    • Elimination Half-Life: 3 hrs

Administration

  • PO Dosing
    • Take with food
  • Hepatic Dose Adjustment
    • Nt recommended for patients with liver disease
  • Renal Dose Adjustment
    • Not recommended for patients with end-stage renal disease (or on hemodialsis)

Dose Adjustment

  • Hepatic
    • Child-Pugh Class A and B (Mild-Moderate Impairment): use with caution
    • Child-Pugh Class C (Moderate Impairment): not recommended
  • Renal: use with caution
    • CrCl <30 mL/min or End-Stage Renal Disease Requiring Hemodialysis: not recommended

Adverse Effects

Allergic/Immunologic Adverse Effects

  • Angioedema (see Angioedema, [[Angioedema]]): cases have been reported (occurs in <1% of cases)

Dermatologic Adverse Effects

  • Photosensitivity: occurs in 9-12 % of cases
  • Rash: occurs in 29-30% of cases

Gastrointestinal Adverse Effects

Neurologic Adverse Effects

  • Dizziness (see Dizziness, [[Dizziness]])
  • Fatigue (see Fatigue, [[Fatigue]])
  • Headache (see Headache, [[Headache]]): occurs in 10-22% of cases
  • Insomnia (see Insomnia, [[Insomnia]])

References

  • Pirfenidone inhibits PDGF isoforms in bleomycin hamster model of lung fibrosis at the translational level. Am J Physiol 1999;276:L311-L318
  • Effects of pirfenidone on transforming growth factor-beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther 1999;291:367-373
  • Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther 1999;289:211-218
  • Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest 2004;125(6): 2169-2174 [MEDLINE]
  • CAPACITY 004 + 006 Trials: Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011 May 21;377(9779):1760-9. doi: 10.1016/S0140-6736(11)60405-4. Epub 2011 May 13 [MEDLINE]
  • ASCEND Trial: A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2083-92 [MEDLINE]