Transcript Pirfenidone

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
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 absorption
the 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
• 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
(Raghu, AJRCCM 1999;159:1060)
Pirfenidone, 24 months
FVC
DLCO
TLC
SpO2
O2
(Raghu, AJRCCM 1999;159:1060)
FVC decline
Grouped analysis
% patients with ΔFVC > 10%
2403 mg Placebo
21%
31%
P
0.003
 Progression free survival
RR=0.74 P=0.025
 Distance 6MWT
Δ=24m P=0.009
 Positive trend for mortality
reduction
(Noble, Lancet 2011;377:1760)
Pirfenidone
• Pirfenidone:
– Antifibrotic, antioxidant, anti-TNF
– Different experimental models :heart, lung, kidney fibrosis
• A series of four randomized controlled studies: (>1100 patients)
Pirfenidone
dosage
N
Changes in VC
decline/placebo
Ref
Azuma
1800 mg/d
Placebo
72
35
ΔVC 100 ml (9mo)
AJRCCM
2005
Taniguchi
1800 mg/d
1200 mg/d
Placebo
108
55
104
ΔFVC 70 ml (12 mo)
ERJ 2010
PIPF 004
2403 mg/d
1197 mg/d
Placebo
174
174
87
ΔFVC =4% pred.
(12% vs 8%)
72 wks
Noble,
Lancet 2011
PIPF 006
2403 mg/d
Placebo
171
173
NS
Noble,
Lancet 2011
Ascend trial: PRESS RELEASE
At 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 INHIBITORS
Amiodarone
Propafenone
Ciprofloxacin
CYP2 C9 INHIBITORS
Amiodarone
Fluconazole
CYP2 D6 INHIBITORS
Paroxetine
Fluoxetine
CYP2 C19
INHIBITORS
Chloramphenicol
The concomitant use of CYP1 A2 INDUCERS may result in
decreased plasma levels of Pirfenidone
CYP1 A2 MODERATE
INDUCER
Omeprazole
CYP1 POTENT INDUCER
Rifampicin
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, mildmoderate 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