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FOCUS ON PIRFENIDONE. Venerino Poletti Ospedale Morgagni Forlì. 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 - PowerPoint PPT Presentation
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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
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