inhaled prostacyclins-usefulness and practility
TRANSCRIPT
Usefulness and Practicality
Sarfraz Saleemi MDKing Faisal Specialist Hospital & Research Center
Pulmonary hypertension - historical perspective
• Ibn Nafees – described pulmonary circulation in ~1250
• Dresdale et al, 1951
– Reported three patients with unexplained pulmonary hypertension
– Clinical, hemodynamic, and pathological features
– Coined the term Primary Pulmonary Hypertension (PPH )
– First attempt at treatment using tolazoline(Priscoline), an adrenergic inhibitor
Dresdale, Am J Med, 1951Dresdale, Bull NY Acad Med, 1954
Humbert M et al. N Engl J Med. 2004;351:1425-1436.
Targets for current PAH-specific therapy
Big Endothelin
Endothelin-converting
Enzyme
EndothelinReceptor A
EndothelinReceptor B
Vasoconstrictionand
Proliferation
EndothelinReceptor
Antagonists
Endothelin-1
Endothelin Pathway
Arginine
Nitric OxideSynthase
Vasodilatationand
Antiproliferation
Nitric Oxide
cGMP ExogenousNitric Oxide
Phosphodiesterase Type-5
PhosphodiesteraseType-5 Inhibitors
Nitric Oxide Pathway
Arachidonic Acid
ProstacyclinSynthase
Vasodilatationand
Antiproliferation
Prostacyclin
cAMP
ProstacyclinDerivatives
ProstacyclinDerivatives
Prostacyclin Pathway
Group 1 PAH
<1995 1995 2001 2002 2004 2005 2007 2009 2013
CCBAnticoagulationDigitalisDiuretics
IV Epoprostenol
Bosentan
SC Treprostenol
IV Treprostenol
Inhaled Iloprost
Sildenafil
Ambrisartan
Tadalafil
Inhaled Treprostinil
Macitentan
Riociguat
Pulmonary Hypertension Treatment Timeline
IV Sildenafil
Dysregulated prostacyclin pathwayin pulmonary hypertension
Voltage gatedK+ channel
Reduced prostacyclin synthase in PH
Tuder et al. Am J Respir Crit Care Med 1999,159:1925
Pharmacological targets of prostacyclin
ArteriesSmooth muscle cells
FibroblastsEndothelial cells
LeucocytesMonocytes, macrophages,polymorphonuclear cells,
T cells
Platelets
Gomberg-Maitland M, Olschewski H. Eur Respir J 2008;31:891–901.
VasodilatationAnti-
inflammation
MAPK
iNOS Matrix secretion
Anti-proliferation
Anti-coagulation
Prostacyclin
Anti-inflammatory/Anti-proliferative
Prostacyclins for PH
Prostacyclin Approved
IV Epoprostenol iPAH, PAH-CTD (USA, Canada) 1995PAH (EU) 1996
Inhaled Iloprost PAH (USA) 2004iPAH (EU)
IV Iloprost iPAH, PAH-CTD, CTEPH (New Zealand)
SC Treprostenol PAH (USA, Canada) 2002iPAH (EU)
IV Treprostenol PAH (USA, Canada) 2004
Inhaled Treprostenol PAH (USA) 2009
Beraprost oral PAH (Japan, Korea)
Treprostinil oral – resubmitted for approval in Sep 2013
awaiting response in March 2014
Epoprostenol- Discovered in 1976 by the Nobel Prize-winning team of John Vane
Inhaled Prostacyclins –selective action
muscular
Partly muscular
Partly intermediate
intermediate
Pericyte level
0.5–3 μm
1. Olschewski H et al. Ann Intern Med 1996;124:820–24; 2. Olschewski H et al. Chest 2003;124:1294–304;
3. Bayer Pharma AG. Ventavis (inhaled iloprost) summary of product characteristics, 2012.
Inhaled iloprost
3
4
5
50
75
CO
(L
/min
)PA
P
(mm
Hg)
MA
P
(mm
Hg)
0 30 60 90
Minutes
MAP
PAP
CO
120
80
2.8 μg of iloprost over 15-minute
inhaled Prostacyclin: selective action
inhaled Prostacyclin: selective action
No significant V/Q mismatchSelectively dilates pulmonary arteries vs systemic arteriesSelectively dilates arteries in well-ventilated vs poorly ventilated areas
. 1. Ghofrani HA. Nat Rev Drug Discov 2006;5:689–702
2. Krug S et al. Vasc Health Risk Manag 2009;5:465–74 3. Olschewski H et al. Ann Intern Med 1996;124:820–4
Normal lung: V/Q matching PH lung: V/Q mismatch
Blood flow
Efficient oxygenation
Blood flow
Poor oxygenation
Chest 2003;124;1294-1304
inhaled Prostacyclin: selective action
FDA approved inhaled Prostacyclins
Iloprost
Treprostinil
ACCF/AHA Consensus PAH Treatment Algorithm
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Atrial septostomyLung transplant
Reassess – considercombo-therapy
ERAs or PDE-5 Is (oral)
Epoprostenol or Treprostinil (IV)
Iloprost (inhaled)
Treprostinil (SC)
No
Anticoagulate ± Diuretics ± Oxygen ± Digoxin
Sustained Response
Positive
Oral CCB
Continue CCB
Yes
Negative
Lower Risk
Epoprostenol or Treprostinil IV
Iloprost (inhaled)ERAs or PDE-5 Is (oral)
Treprostinil (SC)
Higher Risk
Investigational Protocols
Acute Vasoreactivity Testing
Inhaled Iloprost
• Iloprost is a carbacyclin analog of prostacyclin• Plasma half-life of 20-30 min • Dose 2.5-5 μg 6-9 times • Aerosolized particles (median diameter 0.5–3 μm)
Apprved Nebulizer Devices for Iloprost
Halolite prodose I-NEB Venta-NEB
Inhaled iloprost
Compact, portable, lightweight, hand-held nebulizerRuns on 2 AA batteries, Accurate, Quiet.Vibrating Mesh Technology.Continuous Delivery system.
Omron- MicroAir- NE-U22VThe I-neb™ AAD® system
• Compact, portable, lightweight, hand-held nebulizer
• Delivers precise individualized dosing with continuous monitoring and adjustment
Inhaled iloprost – Dose adjustment
Dose per inhalation session: 2.5 µg or 5 µg
Frequency of dosing?
Bayer Pharma AG. Ventavis (inhaled iloprost) summary of product characteristics, 2012.
Initiateinhaled iloprost
2.5 µg dose
Uptitrateinhaled iloprost
5 µg dose
Well tolerated?
Well tolerated?
Poorlytolerated?
Maintain 5 µg
Downtitrate: 2.5 µg
6–9 inhalations per day
According to individual need and tolerability
Idiopathic Pulmonary Arterial Hypertension and Inhaled Iloprost: Good Night Rebound Effects?
Duration of action (30–120 min)
??Risk of rebound pulmonary hypertension (RPH) at night during treatment free period.
5 IPAH patients (NYHA III) on chronic iloprost treatment .
Hemodynamics by a Swan-Ganzcatheter during day and night
No significant RPH during the
off-medication time at night
PAP and PVR did not exceed the maximal day time values.
Respiration 2007;74:498–502
Lack of desensitization
• Inhaled iloprost avoids continuous receptor activation and desensitization of acute vasodilatation response does not occur
• Acute hemodynamic response is maintained for many months
1. Schermuly RT et al. Respir Res 2007;8:4;2. 2. Nilius SM et al. FEBS Lett 2000;484:211–16;
3. Olschewski H et al. Intensive Care Med 1998;24:631–4.
Pre-inhalationPost-inhalation
0
mP
AP
(m
mH
g)
1
20
40
180
Day
60
3600
PV
R (
dyn
•s•
cm
-5)
1
500
1500
180
Day
2000
360
1000
2500
Overview of published clinical studies
1. Olschewski H et al. N Engl J Med 2002;347:322–9; 2. Olschewski H et al. Respir Med 2010;104:731–40; 3. Hoeper MM et al. N Engl J Med 2000;342:1866–70; 4. McLaughlin VV et al. Am J Respir Crit Care Med 2006;174:1257–63; 5. Ghofrani HA et al. Ann Intern Med 2002;136:515–22; 6. Ghofrani HA et al. J Am Coll Cardiol 2003;42:158–64.
Study name Patients Duration Key result
Monotherapy
AIR FC III/IV (n=203)
12 weeksSignificant treatment benefit with
iloprost in patients with severe PAH
AIR-2 FC II/III/IV (n=63)
2 yearsSustained inhaled iloprost improves
predicted 2 year survival
Long-term3 FC III/IV (n=24)
1 year Clinical benefits of inhaled iloprost are sustained over 1 year of therapy
Combination therapy
STEP (bosentan + iloprost)
FC II/III/IV (n=67)
12 weeks Inhaled iloprost + bosentan is well tolerated and effective
Acute iloprost + sildenafil
FC III/IV (n=30)
Acute dose Inhaled iloprost + sildenafil acts synergistically to induce
strong pulmonary vasodilation
Iloprost + sildenafil
FC III/IV (n=14)
1 year Inhaled iloprost + sildenafil improves outcomes in patients with severe PAH
-40
-20
0
20
40
1 2 3 4
Inhaled
Iloprost
Placebo
AIR study
Olschewski H et al. N Engl J Med 2002;347:322–9.
Improvement in 6MWD
Mean
ch
an
ge in
dis
tan
ce w
alk
ed
(m
)
Baseline Week 4 Week 8 Week 12
• In IPAH patients on inhaled iloprost, average increase in 6MWD was 58.8 m longer than for placebo-treated patients
Δ6MWD =36 mp=0.004
STEP study
Inhalediloprost
50
25
Mean
ch
an
ge i
n
dis
tan
ce w
alk
ed
(m
)
Baseline
Week 4
Week 8
Week 12
Placebo0
-25
Δ6MWD =26 mp=0.051
McLaughlin VV et al. Am J Respir Crit Care Med 2006;174:1257–63.
(Bosentan + inhaled iloprost)
AIR study: Aerosilized Iloprost Randomized study
Olschewski H et al. N Engl J Med 2002;347:322–9.
Combined primary endpoint:• Improvement by ≥1 NYHA FC • ≥10% improvement in 6MWD • no deterioration or death
0
5
10
15
20
Inhaled Iloprost
Pati
en
ts (
%)
Placebo
5%
p=0.007
17%
Significant improvement in the combined primary endpoint with inhaled iloprost vs placebo
Efficacy (time to clinical worsening)
• No patients receiving bosentan + inhaled iloprost experienced clinical worsening, compared with 15% of patients receiving bosentan + placebo (p=0.02)
McLaughlin VV et al. Am J Respir Crit Care Med 2006;174:1257–63.
Bosentan + inhaled iloprost1.00
0.75
0.50
0.25
0.00
Wit
ho
ut
cli
nic
al
dete
rio
rati
on
(p
ercen
tag
e o
f p
ati
en
ts)
Bosentan + placebo
Baseline Week 4 Week 8 Week 12
Clinical worsening defined as: death due to PAH, worsening PAH leading to hospitalization or early elimination from the study, necessary additional PAH-specific therapy, lung transplant or atrial septostomy
STEP study
STEP open-label extension: Clinical worsening
• A 3-month delay in adding prostacyclin therapy may negatively affect the clinical result
Olschewski H et al. Eur Resp Rev 2009;18:29–34.
Placebo+ Inhaled iloprost
Bosentan
0 3 6 9 12
Inhaled iloprost
Bosentan
43%
23%
Patients withclinical worseningafter one year
Patients withclinical worseningafter one year
Months
Addition of sildenafil to inhaled iloprost further increased exercise capacity
inhaled iloprost+ oral sildenafil
sil-ilo9-12 mo
treatment interval18 + 4 months
sil-ilo6 mo
sil-ilo3 mo
pre-sililo3 mo
Baseline
180
200
220
240
260
280
300
320
340
360
380
400
6-m
inu
te w
alk
dis
tan
ce (
m)
p=0.002p=0.014
p=0.002+
++
Ghofrani HA et al. J Am Coll Cardiol 2003;42:158–64.
• Inhaled iloprost alone and oral sildenafil alone showed similar efficacy (pulmonary vasodilatory potency)
• Inhaled iloprost and oral sildenafil together acted synergistically to cause strong pulmonary vasodilatation
Acute use study (sildenafil + inhaled iloprost): Hemodynamic outcomes
Ghofrani HA et al. Ann Intern Med 2002;136:515–22.
PVR
(% c
hange f
rom
baseline)
60
NO Iloprost Sildenafil 50 mg
0 60 0 120
-30
-20
-10
0
-50
-40
Time (min)
n = 8
180
NO
0 60 0 60 120
Time (min)
n = 8
Iloprost Sildenafil 50 mg
Iloprost
Inhaled Iloprost in acute right heart failure due to PAH
Age (y) 72 59 52 65 55 48 63
Baseline PH therapy
SC treprostinil
Bosentan SC treprostinil
SC treprostinil
SC treprostinil
Sitaxentan Sitaxentan
NT-proBNP
9,690 10,636 9,340 8,964 1,265 20,239 35,000
J Card Fail. 2011 October; 17(10): 813–818
(7 patients) Hourly inhaled iloprost for 12 hours
Open-label extension of the AIR study – 71 patients
NYHA FC improved in 41% at 1 year & 76% at 3 year
Survival rate:
83% at 1 yr
78% at 2 yrs
58% at 5 yrs (Estimated survival without treatment 32%)
www.clinicalstudyresults.org/ drugdetails/?company_id573&indication_id5854&sort5c.company_name&page51&drug_id52423 December 16, 2008
Long term efficacy of IloprostSurvival
Transition from Parenteral prostacyclin toinhaled Iloprost (n=37)
Pulmonary circulation April-Iune 2013
iloprost is not approved for use in childrenData on its use in the pediatric PAH population is limited.
22 children median age 11.5 years (range, 4.5–17 i PAH & PAH-CHD19 On background PAH-specific therapyDuration 6 months WHO FC improved in 35% , decreased in 15% and unchanged in 50% Bronchopasm and compliance issue were major limitations
Ivy et al. (2008)
.
A review of 28 studies (most case series) 195 childrenInhaled iloprost has acute effects similar to those of inhaled NO and might have a role in the short-term treatment of pediatric PH, including neonates.This application of inhaled Iloprost is useful especially in countries where inhaled NO is not available
Mulligan and Beghetti,2011
Inhaled Iloprost in Children
Cost effectiveness of inhaled Iloprost (3 year analysis)
Appl Health Econ Health Policy 2012; 10 (3): 175-188
Inhaled Treprostinil (Tyvaso)Administered 4 times daily with Optineb
Maximum 9 breaths 4 times a day
Each breath 6 microgram
1 ampule of inhaled treprostinil enough for the day
whether 3 breaths or 9 breaths 4 times a day.
Discard the remaining dose after last dose of the day
Needs washing of optineb accessories everyday.
%
0
3.0
5.0
10
TRIUMPH[TReprostinil sodium Inhalation Used in the Management of Pulmonary Hypertension]
• 6-minute walk distance (6MWD) ↑ in treprostinil vs. placebo at 12 weeks (21.6 vs. 3.0 m, p = 0.0004); noted as early as 6 weeks (p = 0.0001)
• No difference in Borg dyspnea score, NYHA class, PAH signs and symptoms (p = NS)
• Clinical worsening similar (3% vs. 5%, p = NS)
Trial design: Patients with pulmonary arterial hypertension (PAH) who were symptomatic on bosentan or sildenafil were randomized to either inhaled treprostinil or placebo. Clinical outcomes were assessed at 12 weeks.
Results
Conclusions
•Inhaled treprostinil was associated with improved 6MWD as compared with placebo in symptomatic patients with PAH already on bosentan or sildenafil
McLaughlin W, et al. J Am Coll Cardiol 2010;55:1915-22
Treprostinil(n = 115)
Placebo(n = 120)
(p = NS)
15
30
21.6
3.0
m
06MWD Clinical worsening
5
(p = 0.0004)
Rapid transition from Inhaled Iloprost to Inhaled Treprostinil (n-73)
Cardiovascular Therapeutics 31 (1), 38-44 (Feb 2013)
Treatment satisfaction is associated with improved quality of life in patients transitioned to inhaled treprostinil from iloprost
Chen et al. Health and Quality of Life Outcomes 2013, 11:31http://www.hqlo.com/content/11/1/31
66 subjects with PAH in a single-arm, open-labelMulticenter trial of iTRE following transition from iILO
Treatment Satisfaction Questionnaire for Medication (TSQM)
MDI-Treprostenol vs Nebulized
Pulmonary Pharmacology & Therapeutics 22 (2009) 50–56
39 consecutive patients with moderate to severe PAH were enrolled in anopen label, placebo controlled trial
Treatment of inhaled Treprostinil induced cough
Inhaled anticholinergic
Inhaled steroids
Oral phenol-based analgesic sprays (eg,Chlorasept)
Drinking very cold or warm water before a treatment
Reducing number of breaths per treatment
• Cough
• Flushing
• Headache
• Trismus
• Insomnia
• Nausea
Side Effects of inahled Prostacyclin
• Hypersensitivity to the drug
• Patients with an increased risk of hemorrhage
• Severe IHD or unstable angina
• Myocardial infarction within the last 6 months
• CVA (TIA or stroke) in the previous 3 months
• Veno-occlusive disease
Relative contraindications to inhaled prostacyclins
Summary
• Inhaled Prostacyclin is an effective treatment of pulmonary arterial hypertension
• Inhaled Prostacyclin causes rapid improvement of pulmonary hemodynamic which is maintained even after long duration due to lack of desensitization
• Inhaled Prostacyclin causes vasodilatation of the well ventilated parts of lung so results in better oxygenation
• Few systemic adverse effects due to selective action • Avoids infection and localized site pain of parenteral
therapy • No involvement of CYP450 so minimal potential for
interaction with drugs metabolized by the liver• Frequent dosaging and preparation time is a major
disadvantage • Cough and facial flushing are the commonest side effects
Thanks
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