session 7: therapy update€¦ · (28.7 to19.3; p = .0002) loading dose:0.4 mg/kg...
TRANSCRIPT
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Dra. Maria Jesús del CerroPediatric Pulmonary Hypertension Unit “RAMON Y CAJAL University Hospital.
Madrid, Spain
SESSION 7: THERAPY UPDATE
TARGETED TREATMENTS FOR PHVD
AntagonistsEndothelinReceptors
(ERA)
Prostacyclins
Inhibidores5-PDE
SildenafilTadalafil
BOSENTAN AMBRISENTANMACITENTAN + Guanilate
CiclaseRiociguat
EpoprostenolTreprostinilIloprost
PHOSPHODIESTERASES FOR PHVD
5- PDEINHIBITORS
SildenafilTadalafil
Vardenafil
� 5-PDE high concentrationin smooth muscle cells of the lung vasculature
� PDE (1-11) family of enzymes ControllingcGMP levels.
� PDE block leads toincrese in cGMP.
� Vasodilatationmediatedby NitricOxide
Phosphodiesterase Type 5 Is Highly Expressed in the Hypertrophied Human Right Ventricle, and Acute Inhibitionof Phosphodiesterase Type 5 Improves. Contractility. (Circulation. 2007;116:238-248.)
� 5-PDE highly expressed in human hypertrohied RV inhibition of 5PDE improveRV contractility
Sildenafil treatment in stablished RV failure improves s diastolic function and attenuates interstotial fibrosis. Circ Physiol 207; H361-369. 2014
SildenafilSildenafil
� Absorption interfered by food, specially fat food.�Hepatic clearance (cit P450, CYP3A4, CYP3A7 ):
interaction with eritromicine, ketoconazol, itrakonazol…
� INTERACTION WITH BOSENTAN (decreases sildenafil exposure up to 50%)Eur J Clin Pharmacol 2008, Br J Clin Pharmacol 2005
�Half life. 4 hours ORAL ADMINISTRATION EVERY 6-8 HOURS
�Rapid absorption afteroral administration(peak plasma levels
30 min-2 h hours afteroral administration)
�Inter-ethnic variability in PK: Sildenafil exposure much higher in Mexican subjects compared to Caucasians (Flores-Murrieta, 2000)
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SILDENAFIL APPROVED BY EMA In IN 2005 FOR FUNCTIONAL CLASS II/III DOSE: 20 mg/8 hours
Galié and the SUPER study investigators. NEJM 2005
278 adults pts12 weeks trial SILDENAFIL vs placeboRandomised, controlled trial
IMPROVEMENTS IN 6MWDTIMPROVEMENTS IN PVR, and CI
LJ Rubin, Chest 2011
Extension study for 259 adult PAH patientsRandomized to placebo, 20, 40, 80 mg/tid71% monotherapy3 years follow up
No benefit of the 80 mg dose over20 mg dose That was the doseapproved after the SUPER 1
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PAP mmHg
TA (mmHg)
““““SILDENAFILAMELIORATES
EFFECTS OF INHALED NO
WITHDRAWAL”.Anesthesiology1999,91(1):307
cGMP
3 neonatesafter cardiac surgery1 mg por SNG
FIRST REPORTED USE IN PEDIATRICS in 1999…
FOLLOWED BY widespread off-label use of the drug….CASE REPORTS ,
CONTROLLED, NON RANDOMISED… SMALL TRIALS, mostly in IPAH, CHD-PAH, postoperative,…
SildenafilSildenafil
2005
Increase in 6MWDT
Statistically significantImprovement in hemodynamics
16 childrenDose 0.5mg/kg to 1mg/kg/dose
36 children 7.5 + 5.9 yearsCompare iNO and oral sildenafil0.5 mg/kg through nasogastric tubrIn vasoreactivity testing
42% children did not reachdetectable level of sildenafilafter 0.5 mg/kg oral dosesuboptimal absorption of sildenafilin almost half the children
(J Am Coll Cardiol 2010;55:1456–62)
…When detectable, there was no statisticallysignificant difference between the fall in PVRI associated with sildenafil and …
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Oral sildenafil produced significant changes in OI.
Baquero H et al. Pediatrics 2006;117:1077-
1-2 mg/kg/6 hoursNasogastric tube
Small pilot trial PPHN OI> 40, sildenafil (n=7) vs placebo (n=6)
Baquero H et alH Niño Jesus, Barranquilla, Colombia
NO significant systemic hypotension.
2006
36 neonates with PPHN 29 already receiving (iNO). significant improvement in OIafter 4 hours of sildenafil infusionin the higher dose cohorts.
In 4 neonates, sildenafilwas stopped due to adverse events
(28.7 to 19.3; P = .0002)
LOADING DOSE:0.4 mg/kgContinuous infusionin 3 HOURS
MAINTENANCE : 1.6mg/kg/dayContinuous infusionJ Pediatrics 2009
2009
84%
83%4%
Intestinal Neumatosis erectiones
80% Survival at 8 months
0
2
4
6
8
10
12
14
jun 06 sep 06 feb 09 nov 09
Rpa
AP/AO TPG PVRIinitial
PVRIAfter iNO
June 2006
70% 20 12,59 7
Sept2006
82% 27 9 8,28
Febr
200960% 20 7,8 3,4
Bosentán + ARA II
Bosentán + sildenafilo + ARA II
Bosentán + sildenafilo + ARA II +iloprost
TrasplanteJulio 09
13 year old boy restrictive cardiomyopathyAnd severe PH AP: BMT por leuKemia
Sildenafil in Heart TrasplantCandidateswith high PVR
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ORAL SILDENAFIL ASSOCITED WITH SIGNIFICANTIMPROVEMENT IN RV FUNCTIONAND HEMODYNAMICS23 CHILDREN COMPAREDTO OTHER 73 NON TREATED WITH SILDENAFIL
Serdarevic-Pehar and David L. WesselAlberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana
Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski,HypertensionSildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral
Serdarevic-Pehar and David L. WesselAlberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana
Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski,HypertensionSildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral
234 PAH children 1-17 years oldtreatment naïve
Etiology IPAH/HPAH (33%)APAH (67%)
PAH after Surgical repair† (52)Congenital systemic-to-pulmonary shunt with SaO2 ≥88% at rest (62)Postrepair D-transposition of great arteries (3)
Barst R J et al. Circulation 2012;125:324-334
RANDOMISED TO PLACEBO /SILDENAFILMONOTHERAPY
Serdarevic-Pehar and David L. WesselAlberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana
Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski,HypertensionSildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral
Serdarevic-Pehar and David L. WesselAlberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana
Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski,HypertensionSildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral
� Primary “endpoint”:Changes in EXERCISE CAPACITY Peak Oxygen Consumptioncardiorespiratory testing
Body Weight, kg Sildenafil Dose, mg
Low Medium High
≥8 to 20 NA† 10† 20>20 to 45 10 20 40>45 10 40 80
� Secondary “endpoints”:Changes in MPAP, PVRI, CI,
Functional Class
EFFICACY
2012
Barst R J et al. Circulation 2012;125:324-334
AFTER 16 WEEKS OF TREATMENT
at Pfizer DIS on December 9, 2011http://circ.ahajournals.org/Downloaded from
Serdarevic-Pehar and David L. WesselAlberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana
Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski,HypertensionSildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral
Serdarevic-Pehar and David L. WesselAlberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana
Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski,HypertensionSildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral
Primary “endpoint” was met formedium and high doses
Significant increase in Peak Oxygen Consumption(7.7%) y del 9.5%
2011
Barst R J et al. Circulation 2012;125:324-334
AFTER 16 WEEKS
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Barst R J et al. Circulation 2012;125:324-334
Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski,HypertensionSildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral
Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski,HypertensionSildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral
…ALSO DECREASE IN MPAP Y PVRIfor the medium and high dose groups
EMAApproved sildenafilFor pediatric PAH
RECOMENDED DOSES�CHILDREN <20 Kg: 10 mg/8 horas�CHILDREN > de 20 kg: 20 mg/8 horas
Placebon (%)
Headache 8 (13) 5 (12) 6 (11) 12 (16) 23 (13)Pyrexia 1 (2) 3 (7) 8 (15) 9 (12) 20 (12)Upper RTI 4 (7) 5 (12) 9 (16) 7 (9) 21 (12)Vomiting 4 (7) 3 (7) 5 (9) 11 (14) 19 (11)Erections* 0 0 3 (13) 3 (12) 6 (9)Diarrhea 5 (8) 2 (5) 3 (6) 7 (9) 12 (7)Bronchitis 1 (2) 2 (5) 5 (9) 3 (4) 10 (6)Cough 3 (5) 2 (5) 4 (7) 2 (3) 8 (5)Nasopharyngitis 4 (7) 3 (7) 3 (6) 2 (3) 8 (5)Nausea 0 0 4 (7) 4 (5) 8 (5)Pharyngitis 0 3 (7) 3 (6) 1 (1) 7 (4)Dizziness 2 (3) 2 (5) 2 (4) 2 (3) 6 (3)Epistaxis 2 (3) 1 (2) 2 (4) 3 (4) 6 (3)Rhinorrhea 0 0 4 (7) 2 (3) 6 (3)Abdominal pain 1 (2) 0 3 (6) 3 (4) 6 (3)
Low Medium High Combinedn (%) n (%) n (%) n (%)
Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski,HypertensionSildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral
Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski,HypertensionSildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral
Dose related
11 serious AEs2 related to the drugIn high dose (80 mg/tid)Ventricular arrythmia and stridor
STARTS-2EXTENSION STUDYEND POINTS:
SAFETYTOLERABILITY
LONG TERM OUTCOMES
Increased mortality in the group for children weight > 20 kg , AFTER TWO YEARS OF THERAPY in the high dose group
mortality rates9%, low14% medium20% for highDoses groups
FDA Drug Safety Communication: FDA recommends against use of Revatio in children with pulmonary hypertension
Safety AnnouncementAdditional Information for PatientsAdditional Information for Healthcare ProfessionalsData Summary
SILDENAFIL?FDA?AUGUST 2012
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� “Favorable risk–benefit profile for using low-dose sildenafil inchildren with PAH comparable to data from other Registries”.
� “Important differences in baseline () parameters in the high-dose group, includinghigher MPAP , RAP, AND PVRI ”. ….
Who hadn´t been taken into account at enrollment…
� 40% of patients who died were initially classified as FC III or IV at baseline(15% in the remainder of the study group)”….
� “During FU after the 16-week trial, clinical care was not standardized, and informationregarding the clinical course not available beyond survival…”
� “Lack of detailed data beyond survival during FU and the intention-to-treat analysis…limiting the ability to discern factors associated with deaths in the study”…
Am J Crit Care med 2013
� “FOR CHILDREN ALREADY RECEVING SILDENAFIL CAUTIOUS DOWNTITRATION TO THE DOSES RECOMMENDED BY EMA..”
� “FOR NEW PATIENTS INITIATING SILDENAFIL THERAPY CAUTIOUSLY UNTIL THERE IS FURTHER REVIEW OF THE DATA…”.
� “FDA REVIEW IS NOT RELEVANT REGARDING THE SHORT TERM USE OF SILDENAFILIN THE CRITICAL CARE SETTING….”
� “SILDENAFIL MONOTHERAPY IS LIKELY INSUFFICIENT WITH DISEASE PROGRESSION…”
Am J Crit Care Med 2013
PPHNET RECOMMENDATIONS
Circulation. 2014; 129: 1905-1908
Mc Elhinney DBAdressed the caveats of Super study:� Lack of comparison in mortality with the placebo group
� Dose regimes based on Pharmacokinetco data obtained in adults
� Estimation of appropiate dose ranges was inaccurate.
� Survival analysis not adequately adjusted
“MULTIPLE ANALYSIS RAISED UNCERTAINTY ABOUT THE SURVIVAL/DOSE RELATIONSHIP..”
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Al Dodgen
Review of 49 reports on sildenafil use in pediatrics625 children, More than 140 infants.No REPORTED SAEs in infants
31th March 2014
“The benefit-risk profile of Revatiomay be acceptable in individual children…”
� MANY CENTERS STARTED CAUTIOUS DOWN TITRATION OF THE DOSESTO ADJUST TO EMA RECOMENDATIONS
� SILDENAFIL STILL USED AS INITIAL THERAPY FOR NAIVE PATIENTS
� TREND TO EARLIER COMBINATION THERAPY INSTEAD OF INCREASING SILDENAFIL DOSES…
� LET´S LOOK AT OUR OWN DATA…
Sildenafil Dosing And Outcomes : Data from the The Spanish Registry REHIPEDSildenafil Dosing And Outcomes : Data from the The Spanish Registry REHIPED
388 pts treated SILDENAFILMean Follow Up 2.7 + 2.6 y
(range 0-12 y)
mean dose: 3 mg/kg/day RANGE: 0.3-12 mg/kg/day
233 monotherapy
165 Combination
ANALIZED SURVIVAL AND MORTALITY RISK FACTORS� Etiology (NICE groups I to V)� Age at diagnosis � FC at diagnosis � Right atrial pressure � mPAP, cardiac index (CI), PVRI, � sildenafil dosing
(0.5mg/kg/day increase)� Combined treatment
� Etiology (NICE groups I to V)� Age at diagnosis � FC at diagnosis � Right atrial pressure � mPAP, cardiac index (CI), PVRI, � sildenafil dosing
(0.5mg/kg/day increase)� Combined treatment
FOR :� All PH pts(n=249)� PAH pts(n= 159)� Fontan pts(n=139)� PH + FONTAN (n=388)
FONTANGlennn=139
PAHn=159
N=90
To be submitted
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UNIVARIATE ANALYSIS
MULTIVARIATEANALYSIS
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
FONTANFontann=139
PAHn=159
N=90
To be submitted
249 Pts PHVD (NICE GROUPS I TO V)
Data From The Spanish Registry For Pediatric PH Data From The Spanish Registry For Pediatric PH
UNIVARIATE analysis
To be submitted
MULTIVARIATE
159 PAH Pts (NICE GROUP I ) treated with sildenafil
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH UNIVARIATE analysis
MULTIVARIATE analysis
Sildenafil Dosing And Outcomes Data From The Spanish Registry For Pediatric PH
Sildenafil Dosing And Outcomes Data From The Spanish Registry For Pediatric PH
EMA RECOMENDATION10 mg tid < 20 kg20 mg/tid > 20 kg
All pts Ph +Fontan (n=388) PH Nice I to V (n=249)
PAH Nice I (n=159) Fontan I (n=139)
To be submitted
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Sildenafil Dosing And Outcomes Data From The Spanish Registry For Pediatric PH
Sildenafil Dosing And Outcomes Data From The Spanish Registry For Pediatric PH
To be submitted
Dose interval Low dose Medium Dose High Dose8-20 kg < 10 mg tid 10-15 mg tid > 15 mg tid20-45 kg < 15 mg tid 15-30 mg tid > 30 mg tid> 45 kg < 15 mg tid 25-60 mg tid > 60 mg tid
Classifying REHIPED patients according to the STARTS trial dosing…
Dose interval Low dose Medium Dose High Dose8-20 kg NA 10 mg tid 20 mg tid20-45 kg 10 mg tid 120 mg tid 40 mg tid> 45 kg 10 mg tid 40 mg tid 80 mg tid
STARTS trial dosing…
Sildenafil Dosing And Outcomes Data From The Spanish Registry For Pediatric PH
Sildenafil Dosing And Outcomes Data From The Spanish Registry For Pediatric PH
To be submitted
Classifying our patients according to the Starts trial dosing…
ALL pts (PH + Fontan)N=388
Low
Medium
High
P=0.044
MediumHigh
Low
PH Nice I to V + Fontan)N=249
P=0.34
Sildenafil Dosing And Outcomes Data From The Spanish Registry For Pediatric PH
Sildenafil Dosing And Outcomes Data From The Spanish Registry For Pediatric PH
To be submitted
Classifying our patients according to the Starts trial dosing…
PAH Nice I N= 98
MediumLow
High
P=0.135
SO….in this retrospective analysisHIGHER DOSES OF SILDENAFIL WAS NOT AN INDEPENDENT PREDICTOR FOR MORTALITYOur results don´t support a direct relationshipbetween higher doses of sildenafil and worsesurvival in the pediatric patients included inthe Spanish Registry for Pediatric PulmonaryHypertension.
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
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MonoNo therapy
CCB
DualTriple
Survival in Pediatric PAHNew York/Denver/NL cohort
WM Zijlstra et al 6J Am Coll Cardiol 2014;63:2159–9
Sitbon O et al, Eur resp J 2016
Pharmacokinetic Interactions Between PAH-specific Medications
Drug 1 Drug 2 InteractionAmbrisentan None N/A
Bosentan Sildenafil Reduces sildenafil plasma concentrations 63%
Tadalafil Reduces tadalafil Cmax 27% at steady state
Macitentan None N/A
Sildenafil Bosentan Increases bosentan concentrations 50%
Tadalafil Bosentan Increases bosentan AUC <20%
Riociguat Sildenafil, tadalafil Contraindicated due to risk of systemic hypotension
Epoprostenol None N/A
Iloprost None N/A
Treprostinil None N/A
FDA. Package inserts for above products. Accessed at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed December 15, 2013.
� Pharmacokinetic data on childrenobtained IN MONOTHERAPY
� Risk of insufficient plasma levels due toinadequate absorption…. inadequate compliance….pharmacokinetic interactions (BOSENTAN)….
SHOULD WE MONITOR PLASMA LEVELS OF5-PDE INHIBITORS
SPECIALLY WHEN USED IN COMBINATION WITH BOSENTAN?
50 KG WEIGHT 13 YEARS OLD CHILD RECEIVING 20 mg/8 hours + BOSENTAN 125 mg/12 h…DOES HE HAVE ADEQUATE SILDENAFIL LEVELS ???
SILDENAFILO AND BOSENTAN…..Most common oral combination therapy in pediatrics….IS THE PHARMACOKINETIC INTERACTION CLINICALLY RELEVANT?
Hakamata A, et al.
Sild+bos
Sild+ambrisentan
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SILDENAFILO AND BOSENTAN…..Most common oral combination therapy in pediatrics….IS THE PHARMACOKINETIC INTERACTION CLINICALLY RELEVANT?
AMBITION: Ambrisentan-Tadalafil Combination Therapy
Primary Study Endpoint: Time To Clinical Worsening
Eve
nt-F
ree
(%)
Time (weeks)
0 24 48 72 96 120 144 168 192
TADALAFIL+AMBRISENTAN
MONOTHERAPY
Number at risk:
334 pts randomized
PACES-2
500 pts ramdomizedSildenafil
Sild +Bosentan
SILDENAFILO AND BOSENTAN…..Most common oral combination therapy in pediatrics….IS THE PHARMACOKINETIC INTERACTION CLINICALLY RELEVANT?
Sildenafil Dosing And Outcomes Data From The Spanish Registry For Pediatric PH
Sildenafil Dosing And Outcomes Data From The Spanish Registry For Pediatric PH
To be submitted
sildenafilSildenafil
+ bosentan
P=0.107 N= 369 ptsPH + Fontan P=0.41 N= 125 pts
PAH (Nice I)
sildenafil
Sildenafil+ bosentan
???Retrospective DataNo Randomization
Uni & Multivariate analysis…
???Retrospective DataNo Randomization
Uni & Multivariate analysis…
KD Hill et al. Cardiol Young 2016
AUC
Hepatic venous pressure (mmHg)
20 Children Single Ventricle PhysiologyPK after Single IV dose of sildenafilIn the cath lab
ELEVATED HEPATIC VENOUS PRESSURESDECREASED CLEARANCE OF
Des-methyl-sildenafilINCREASING DRUG EXPOSURE
“A patient with High venous pressure receiving a Low dose of sildenafil could be havinga HIGH EXPOSURE EQUIVALENT TO RECEIVING A HIGH DOSE…”
Yokohama Y et al.
50 microlitres of blood
� Optimize dosing for individual pts� Evaluate Interactions in Combination Therapy� Optimize dosing for individual pts� Evaluate Interactions in Combination Therapy
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� PHARMACOKINETICS
� REPORTED EXPERIENCE IN PAH ADULTS
� REPORTED TADALAFIL EXPERIENCE IN PHVD IN CHILDREN
Forgue ST. Br J Clin Pharmacol 2006, 61(3): 280-8� Linear correlationship
between dose and plasma levels(dose proportionality)
� Half life 17 hours.
� Absorption NO affectedby food or fat meals.
� Slightly better availability in the morning
� Near maximal plasma levelsfrom1.5 to 6.5 hours after ingestion
� Steady state after 10 days of oral intake
ONCE DAiLYadministration
Tadalafil Therapy for Pulmonary Arterial Hypertension
Nazzareno Galiè, Bruce H. Brundage, Hossein A. Ghofrani, Ronald J. Oudiz, Gerald Simonneau, Zeenat Safdar, Shelley Shapiro, R. James White, Melanie Chan, Anthony
Beardsworth, Lyn Frumkin, and Robyn J. Barst
Tadalafil Therapy for Pulmonary Arterial Hypertension
Nazzareno Galiè, Bruce H. Brundage, Hossein A. Ghofrani, Ronald J. Oudiz, Gerald Simonneau, Zeenat Safdar, Shelley Shapiro, R. James White, Melanie Chan, Anthony
Beardsworth, Lyn Frumkin, and Robyn J. Barst
Circulation 2009, 119(22):2894-2903
405 adult patientsTreatment naive or on ERA (53%)randomized to placebo/tadalafilDoses from 2.5 mg to 40mg /day
TADALAFIL increasedthe 6MWDT in a dose dependent mannerOnly the dose of 40 mg/24 hoursReached the level of statistical significance (p<0.01
40 mg/day
Kaplan–Meier estimates of the proportion of patient s with clinical worsening.
Galiè N et al. Circulation 2009;119:2894-2903
Tadalafil Therapy for Pulmonary Arterial Hypertensio nNazzareno Galiè, Bruce H. Brundage, Hossein A. Ghofrani, Ronald J. Oudiz, Gerald Simonneau, Zeenat
Safdar, Shelley Shapiro, R. James White, Melanie Chan, Anthony Beardsworth, Lyn Frumkin, and Robyn J. Barst
Tadalafil Therapy for Pulmonary Arterial Hypertensio nNazzareno Galiè, Bruce H. Brundage, Hossein A. Ghofrani, Ronald J. Oudiz, Gerald Simonneau, Zeenat
Safdar, Shelley Shapiro, R. James White, Melanie Chan, Anthony Beardsworth, Lyn Frumkin, and Robyn J. Barst
295 completed the10 months extension study
Tadalafil 40 mg improved :�time to clinical worsening
(p=0.041)�Incidence of clinical worsening(68% risk reduction)
�Health related QOLCommon side effects: headache, mialgia, leg pain
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Initial experience with tadalafil in pediatricpulmonary arterial hypertension.Initial experience with tadalafil in pediatricpulmonary arterial hypertension.� 4 IPAH naive treatment pts� 29 CHILDREN transitioned from
(27 combined therapy) sildenafil
3.4 ± 1.1 mg/kg/d,
Pediatr Cardiol. 2012 Jun;33(5):683-8.Improvement in FC, MPAP and PVRI , PVRI/SVRI compared to sildenafilin catheterized pts (n=14)
6% discontinued tadalafilDue to adverse effects
ONGOING PEDIATRIC CLINICAL TRIALS
LVIG LVHV
Children < kg: 10 mgChildren 20-40 kg: 20 mgChildren> 40 kg: 40 mg
tadalafil1.0 ± 0.4 mg/kg/day
16 ADOLESCENTS /YOUNG ADULTS WITH EISENMNGER SYNDROMEHemodynamic effect of tadalafil 1 mg/kg up to 40 mg
After 90 min (acute effect)after 12 weeks treatment
Improvement in FC and Hemodynamics
2012-201318 children PAH in CHD(14 Eisenmenger syndrome)SILDENAFIL: 54.5 ± 29.3 mg/day (20-100 mg/day)for 4.5 years.Transitioned from sildenafilto tadalafilEVALUATED AFTER 6 WEEKS of tadalafil
Iran Improvemnt in 6MWDT
Pediatr Cardiol Nov 2013
increase in Oxygen Sat
Similar profileof side effects
Experience TADALAFIL Ramón y Cajal University Hospital
• 34 pts:• 30 transition from sildenafil, 4 new treatments• Dose: 1 mg/kg/day (10-40 mg)• AGE: mean 20,6 años Range (5 -56 years ).
<18 years > 18 years (CHD)16 pts 18 pts
• Functional Class: II/III• 10 pts (31,3%) Down Syndrome. • Gender: 17 males (50%) y 17 females (50%).
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Diagnosis:
-10 (28,6%) Corrected CHD
-12 (34,3%) Eisenmenger
-1 (2,9%) Fontan
-4 PH Lung disease (3 BPD)
- 7 (20%) HAPI
Experience TADALAFIL Ramón y Cajal University Hospital
Experience TADALAFIL Ramón y Cajal University Hospital
� Increase in 6MWDT from 441 to 481
� IMPROVED COMPLIANCE in all
� AES: � Only 1 pt interrupted treatment
(increased menstrual bleeding)
� 1 pt needed decrease in dose (headache)
� 1 pt slower titration (leg pain)
0100200300400500600
PRE POST
6MWDT
� PDE INHIBITORS : METABOLIC PATHWAY IN PH VASODILATATION and remodellingPOSSIBLE ADITIONAL BENEFIT ON RV CONTRACTILITY OF 5PDE inbibitors?
� SILDENAFIL : WIDESPREAD CLINICAL EXPERIENCE IN ITS USE
CONTROVERSY ABOUT THE FDA WARNING
Different implications in different countriesLESSONS LEARNED…FUTURE DESIGN OF TRIALS…
IN SPITE OF FDA WARNING….ONGOING USE IN INFANTS, NEONATES, PAH, Fontan
ACUTE PH (postoperative, PPHN, PH crises…
IN MANY COUNTRIES sildenafil LOWER COSTthan other 5PDE inhibitors
� PHARMACOKINETICS :ONCE A DAY ADMINISTRATION CAN: IMPROVE COMPLIANCE
PROVIDE MORE STABLE LEVELS
� HEMODINAMIC ADVANTAGE over sildenafil??
METABOLIC INTERACTIONS BETWEEN 5PDE INHIBITORS AND OTHER DRUGS (BOSENTAN) NEED TO BE CONSIDERED!!!!
WE NEED : PHARMACOKINETIC DATA - ON COMBINED THERAPIES - ON SPECIFIC SITUATIONS (e: Right Heart failure, Fontan, Neonates..- RESEARCH IN PHARMACOGENETICS !!!!
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RIOCIGUAT DUAL MECHANISM OF ACTION:�Sensitizes sGC to endogenous NO (stabilization of NO–sGC binding)�Directly stimulates sGC independently of endogenous NO
RIOCIGUAT TARGETS A DIFFERENTPART OF THESAME PATHWAY That 5 PDE inhibitors…
� THE ACTIVITY OF SILDENAFILdepends on the presence of an INTACT NO- SGC –CGMP axis.
� its efficacy may be limited in the presence of low NO levels (e.: interaction of NO with anion
superoxide peroxynitrite
Altered redox state of sGC
Inflammationstate
Unresposive to endogenos NOand other NO releasing drugs
� RATIONALE FOR THE USE OFNO independent activatorsof soluble guanilate ciclase
Rubin et al
Increases in 6MWDT and WHO functional classLONGER TIME TO CLINICAL WORSENING
321 patientsSustained Improvementsin 6MWDT
NO EXPERIENCE IN PEDIATRICS
CLINICAL TRIAL ONGOING
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From animal models …REDUCING RV HYPERTROPHY and Muscularization of peripheral arteries in rats monocrotaline model of PH
TO PHASE I:safety , Pharmacokinetic &
pharmacodynamic studies in healthy volunteers
In vitro…concentrations of 0.1–100 l mol/LRiociguat stimulated recombinant rat sGC,with a 2- to 73-fold
increase in activity from basal levels…
� RIOCIGUAT DEVELOPMENT
Eur Respir J. 2008;32(4):881–91.
J Clin Pharmacol. 2008;48(8):926–34
…TO PROOF OF CONCEPT STUDY:Dose-dependent decrease in PVR, increase in Cardiac output in adult patients with CTEPH or PAH..greater effect than iNO
…TO PHASE –II STUDIES in PAH and CTEPH
Eur Respir J. 2009;33(4):785–92.
� Rapid absorption, minimally interfered by food.� Maximum plasma concentration (Cmax ) in 1–1.5 h � Pharmacokinetics linear and dose proportional� High absolute bioavailability 94 %.� Hepatic & lung metabolism to less active metabolites� Half-life : 7-12 hours
� CYP and P-glycoprotein/BCRP inhibitors:ketoconazole/itraconazole,ritonavir, CyA)
� CYP3A4 inducersrifampin, phenytoin, carbamazepine, phenobarbitoneSMOKING
No clinically relevant pharmacokinetic interactions werediscovered with warfarin, aspirin, midazolam, sildenafil.
concentration of riociguat
� NITRATES, � NITRIC OXIDE DONORS� PHOSFODIESTERASE
INHIBITORS� PREGNANCY
riociguat concentration
� Multicenter, randomized, controlled study261 patients with unoperable CETPH or persistent/recurrent after surgery
� Placebo/riociguat for 6 weeks
�Primary end point: 6MWDT � Secondary:
nt-Pro BNP, PVR, FCTime to clinical worsening
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…Phase III TrialsEfficacy of Riociguat tested in
CTEPH PAH Ghofrani HA, et al Ghofrani HA, et al
0.5 to 2. 5 mg t.i.d
N= 261 patients
CHANGE IN FUNCTIONAL CLASS Tolerability of riociguat
0.5-2.5 mg tidfrom Chest- 1 and Patent- 1 (pooled data)
FRACTURE OF PATELLA
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Simmoneau Eur Resp J 2014 Rubin et al
324 PAH patients followed after PATENT-1Dose uo to 2.5 mg t.i.dIncreases in 6MWDT and WHO functional class
NO EXPERIENCE IN PEDIATRICS
CLINICAL TRIAL ONGOING
Rubin et al Thank you foryour attention…
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249 Pts PHVD (NICE GROUPS I TO V)treated with sildenafil
< 3mg/kg/day
< 3-4mg/kg/day
> 4mg/kg/day
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
NYHA FC MEAN SILDENAFIL DOSE mg/k/day
n SD
NYHA I-II 2.6 82 1.48NYHA III 3.2 60 1.99NYHA IV 4.1 36 2.67Total n pts 3.17 178 2.01
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
388 patientstreated with SILDENAFIL
SILDENAFIL DOSINGas potential risk factor
for mortality
mean dose: 3 mg/kg/day RANGE: 0.5-12 mg/kg/day
233 monotherapy
165 Combination
FONTANGlennn=139
PAHn=159
n=90
111 GLENN or FONTAN ptstreated with sildenafil
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
UNIVARIATE analysis
MULTIVARIATE ANALYSIS
HR (95% IC) p-value MPAP 1.23 (1.01-1.50) 0.039
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
EMA RECOMENDATION:10 mg/8 hours children < 20 kg weight20 mg/8 hours children > 20 kg weight
289 PEDIATRIC PATIENTS(PH and Fontan pts )RECEIVING SILDENAFIL
HIGHER thanEMA recomendatio
according toEMA recomendation
p-valor log-rank ratio = 0.009
FONTANGlennn=111
PAHn=109
n=61
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178 Pts PHVD (NICE GROUPS I TO V) treated with sildenafil
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
HIGHER thanEMA recomendation
according toEMA recomendation
p-valor log-rank ratio = 0.094
EMA RECOMENDATION:10 mg/8 hours children < 20 kg weight20 mg/8 hours children > 20 kg weight
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
EMA RECOMENDATION:10 mg/8 hours children < 20 kg weight20 mg/8 hours children > 20 kg weight
109 PAH PEDIATRIC PATIENTSRECEIVING SILDENAFIL
HIGHER thanEMA recomendation
according toEMA recomendation
p-valor log-rank ratio = 0.599
P=0.59
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
Sildenafil Dosing And Outcomes In Pediatric Pulmonary Hypertension:
Data From The Spanish Registry For Pediatric PH
EMA RECOMENDATION:10 mg/8 hours children < 20 kg weight20 mg/8 hours children > 20 kg weight
111 Fontan or Glenn ptsRECEIVING SILDENAFIL
FONTANGlennn=111
HIGHER thanEMA recomendatio
according toEMA recomendation
P=0.44
Sildenafil Dosing And Outcomes Data From The Spanish Registry For Pediatric PH
Sildenafil Dosing And Outcomes Data From The Spanish Registry For Pediatric PH
To be submitted
Classifying our patients according to the Starts trial dosing…
ALL pts (PH + Fontan)N=388
Low
Medium
High P=0.044
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Douwes JM et al. Heart 2014
Sild add to bosentanN=15
Bosentan monoN=9
EMA doses
� MILRINONE IN PPHN AND POSTOPERATIVE CARE
48 CHILDREN postop shunt closureassigned to: Iv milrinone (n=16)Oral sildenafil (n=16)Combination (n=16)Milrinone group Lower SPP/SAo P ratio
than sildenafilLower rate in PH crisesLower ICU stay
Peiravian F.Iranian J Pediatr 2013
� Open label study of milrinone in neonates PPHN and suboptimalresponse to I NO
� intravenous loading dose of milrinone(50 μg/kg) over 60 mins
� maintenance infusion (0.33-0.99 μg/kg/min) for 24-72 hrs
Echo: lower PAP,improved CARDIAC output, reduced bidirect or right-left shunting(p < 0.05) after milrinone treatment.
NEED OF RAMDOMIZED TRIALMc Namara Pediatr Crit Care Med 2013