Pirfenidone

Indicated for idiopathic pulmonary fibrosis.

A pyridine.

Acts through anti-inflammatory and anti-fibrotic pathways, although it’s exact mechanism of function is not known.

Has a significant greater effect than placebo on forced vital capacity studies.

A medication used for the treatment of idiopathic pulmonary fibrosis.

It works by reducing lung fibrosis through downregulation of the production of growth factors and procollagens I and II.

Studies have shown that it reduces fibroblast proliferation, inhibits transforming growth factor beta stimulated collagen production, and reduces the production of fibrogenic mediators such as transforming growth factor beta.

Trade names Esbriet, Pirespa, Etuary

Oral agent.

Protein binding 50–58%.

Metabolism is hepatic with 70–80% CYP1A2-mediated and minor contributions from CYP2C9, CYP2C19, CYP2D6 and CYP2E

Elimination half-life 2.4 hours.

Excretion by urine is 80%.

In Mexico it has been approved on a gel for the treatment of scars, fibrotic tissue,and skin ulcers.

Adverse side effects:

Gastrointestinal with dyspepsia, nausea, gastritis, gastroesophageal reflux disease and vomiting.

Skin-causing photosensitivity reactions, rash, pruritus and dry skin.

Hepatic dysfunction with elevated LFT’s.

Dizziness and fatigue

Weight loss

Side effects can be reduced if the drug is taken after meals.

Periodic monitoring of hepatic enzyme levels is required during therapy.

The drug is contraindicated with severe hepatic impairment.

It is metabolized through the CYP1A2 enzyme pathway, any drug which inhibits this enzyme is likely to precipitate the toxicity of pirfenidone:

Inhibitors of CYP1A2 such as ciprofloxacin, amiodarone and propafenone should be used with caution.

Some pirfenidone is also metabolized by cytochrome P450 enzymes other than CYP1A2 and inhibitors of other cytochrome P450 enzymes such as fluconazole (CYP2C9), chloramphenicol (CYP2C19), fluoxetine and paroxetine (both CYP2D6) should be used with caution.

Moderate inducers of CYP1A2 such as omeprazole should be used with caution since they might reduce the circulating plasma levels of the drug.

Cigarette smoking causes increased clearance of pirfenidone by inducing CYP1A2, thereby decreasing exposure to the drug.

Pirfenidone has well-established antifibrotic and anti-inflammatory properties.

Aministered orally.

Food significantly reduces absorption.

The drug is to be taken after food, to reduce the nausea and dizziness associated with the drug.

The drug is around 60% bound to plasma proteins, especially to albumin.

Up to 50% of the drug is metabolized by hepatic CYP1A2 enzyme system to yield 5-carboxypirfenidone, an inactive metabolite.

Almost 80% of the administered dose is excreted in the urine within 24 hours of intake.

It attenuates bleomycin-induced pulmonary fibrosis.

On a phase III trial Pirfenidone 1800 or 1200 mg/day reduced the mean decline in vital capacity from baseline to week 52 compared with placebo in patients with idiopathic pulmonary fibrosis.

Progression-free survival was also improved with pirfenidone compared with placebo.

In randomized, double-blind, placebo-controlled Phase III studies patients with idiopathic pulmonary fibrosis were randomly assigned to treatment with oral pirfenidone or placebo for a minimum of 72 weeks: Mean change in FVC at week 72 was –8.0% in the pirfenidone 2403 mg/day group and –12.4% in the placebo group, a difference of 4.4%.

Clinical studies indicate pirfenidone significantly reduced the progression of idiopathic pulmonary fibrosis as measured by change in percent predicted forced vital capacity from baseline to week 52.

In an analysis of the pooled population of 1,247 subjects from three studies showed that the risk of all-cause mortality was reduced by 48% in the pirfenidone group compared to the placebo group.

A review by the Cochrane Collaboration concluded it improves progression-free survival and, to a lesser effect, pulmonary function in patients with idiopathic pulmonary fibrosis.