Venerino PolettiOspedale Morgagni Forlì

FOCUS ON PIRFENIDONE

Conflicts of Interest

• Member of the Advisory Borad of Intermune

PIRFENIDONE & LUNG *has antifibrotic and anti-inflammatory anti-oxidant properties in various in vitro systems and animal models of pulmonary fibrosis,

*attenuates fibroblast proliferation, production of fibrosis-associated proteins and cytokines, and the increased biosynthesis and accumulation of extracellular matrix in response to cytokines such as transforming growth factor-β.

PHARMACOKINETICS

Pirfenidone is administered orally.

Though the presence of food significantly reduces the extent of absorptionthe drug is to be taken after food, to reduce the nausea and dizziness

It is –around 60%- bound to plasma proteins, mainly to albumin

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

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

Pirfenidone: the past

(Raghu, AJRCCM 1999;159:1060)

• 54 IPF patients• Deterioration with steroids ± I°S• TLC 58 ± 16 %• DLCO 34 ± 17 %

Pirfenidone: 40 mg/kg (maxi 3600 mg/j)Stop CS and I°S within 8 weeks

Pirfenidone, 24 months

FVC TLC

DLCO

(Raghu, AJRCCM 1999;159:1060)

SpO2 O2

(Noble, Lancet 2011;377:1760)

FVC declineGrouped analysis

% patients with ΔFVC > 10%

2403 mg Placebo P

21% 31% 0.003

Progression free survival RR=0.74 P=0.025

Distance 6MWT Δ=24m P=0.009

Positive trend for mortality reduction

Pirfenidone

• Pirfenidone:– Antifibrotic, antioxidant, anti-TNF– Different experimental models :heart, lung, kidney fibrosis

• A series of four randomized controlled studies: (>1100 patients)

Pirfenidonedosage

N Changes in VC decline/placebo

Ref

Azuma 1800 mg/dPlacebo

7235

ΔVC 100 ml (9mo) AJRCCM 2005

Taniguchi 1800 mg/d1200 mg/dPlacebo

10855104

ΔFVC 70 ml (12 mo) ERJ 2010

PIPF 004 2403 mg/d1197 mg/dPlacebo

17417487

ΔFVC =4% pred.(12% vs 8%)72 wks

Noble, Lancet 2011

PIPF 006 2403 mg/dPlacebo

171173

NS Noble,Lancet 2011

Ascend trial: PRESS RELEASEAt Week 52, 16.5% of patients in the pirfenidone group experienced an FVC decline of 10% or more or death, compared with 31.8% in the placebo group, representing a 47.9% reduction in the proportion of patients who experienced a meaningful change in FVC or death. 

Additionally, at Week 52 the data demonstrated that 22.7% of patients in the pirfenidone group experienced no decline in FVC, compared with 9.7% in the placebo group, representing a 132.5% increase in the proportion of patients whose FVC did not decrease between Baseline and Week 52.

PFS is a measure of time before death or a disease-progression event.  A PFS event was defined in the protocol as any of the following: death, percent predicted FVC decrement of 10% or greater or 6MWD decrement of 50 meters or greater.  In ASCEND, pirfenidone reduced the risk of death or disease progression by 43% compared to placebo (Hazard Ratio [HR]=0.57; 95% confidence interval, 0.43-0.77; p=0.0001).

PIRFENIDONE IN IPF:PRACTICAL ISSUES

Posology and Administration: METHOD OF ADMINISTRATION

Posology and Administration: DOSE TITRATION

PATIENTS ASSESMENT BEFORE PIRFENIDONE TREATMENT: LABORATORY WORK-OUT

- BLOOD CELL COUNT

- LIVER FUNCTION TESTS -> SEVERE HEPATIC IMPAIRMENT IS A CONTROINDICATION – CAUTION IF MILD-MODERATE HEPATIC IMPAIRMENT

- SCREENING FOR HEPATITIS B AND C -> if positive CAUTION SHOULD BE USED

- RENAL FUNCTION TESTS -> SEVERE RENAL IMPAIRMENT (Cl creat <30%) IS A CONTROINDICATION

PATIENTS ASSESMENT BEFORE PIRFENIDONE TREATMENT: CONCOMITANT MEDICATIONS

Fluvoxamine is the ONLY CONTROINDICATED DRUG

Patients taking CYP MODERATE AND STRONG INHIBITORS should be monitored closely

CYP1 A2 INHIBITORSAmiodaronePropafenoneCiprofloxacin

CYP2 C9 INHIBITORSAmiodaroneFluconazole

CYP2 C19 INHIBITORS

Chloramphenicol

CYP2 D6 INHIBITORSParoxetineFluoxetine

The concomitant use of CYP1 A2 INDUCERS may result in decreased plasma levels of Pirfenidone

CYP1 A2 MODERATE INDUCER

Omeprazole

CYP1 POTENT INDUCERRifampicin

Posology and Administration: DOSE ADJUSTMENT FOR SAFE USE

Posology and Administration: DOSE ADJUSTMENT FOR SAFE USE

Posology and Administration: DOSE ADJUSTMENT FOR SAFE USE

ALT, AST and BILIRUBIN should be monitored MONTHLY FOR THE FIRST 6MONTHS AND THEN EVERY THREE

MONTHS.

Posology and Administration: DOSE ADJUSTMENT FOR SAFE USE

PIRFENIDONE:SUMMARY-Pirfenidone requires a diagnosis of definite IPF, mild-moderate stage.

-Take sufficient time for patient counseling, plan subsequent visits and give the patient a number to stay in contact

-Dosage adjustments and temporary interruptions are sufficient to resolve the majority of mild to moderate side effects

-Severe drug reactions are unusual (10%) and resolve without sequelae after drug discontinuation

-Pirfenidone significantly reduce the risk of disease progression

- IPF is still a lethal disease, but now is curable