3/11/2017 TARGETED TREATMENTS FOR PHVD SESSION 7: Antagonists - - PowerPoint PPT Presentation

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• Dra. Maria Jesús del Cerro

Pediatric Pulmonary Hypertension Unit “RAMON Y CAJAL University Hospital. Madrid, Spain

SESSION 7: THERAPY UPDATE TARGETED TREATMENTS FOR PHVD

Antagonists Endothelin Receptors

(ERA)

Prostacyclins

Inhibidores 5-PDE Sildenafil Tadalafil

BOSENTAN AMBRISENTAN MACITENTAN + Guanilate Ciclase Riociguat Epoprostenol Treprostinil Iloprost

PHOSPHODIESTERASES FOR PHVD

5- PDE INHIBITORS Sildenafil Tadalafil Vardenafil

5-PDE high concentration in smooth muscle cells of

the lung vasculature

PDE (1-11) family of enzymes Controlling cGMP levels. PDE block leads to increse in cGMP. Vasodilatation mediatedby Nitric Oxide

Phosphodiesterase Type 5 Is Highly Expressed in the Hypertrophied Human Right Ventricle, and Acute Inhibition

• f Phosphodiesterase Type 5 Improves. Contractility. (Circulation. 2007;116:238-248.)

5-PDE highly expressed in human hypertrohied RV inhibition of 5PDE improve RV contractility

Sildenafil treatment in stablished RV failure improves s diastolic function and attenuates interstotial fibrosis. Circ Physiol 207; H361-369. 2014

Sildenafil Sildenafil

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 after

• ral administration

(peak plasma levels 30 min-2 h hours after

• ral 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 pts 12 weeks trial SILDENAFIL vs placebo Randomised, controlled trial IMPROVEMENTS IN 6MWDT IMPROVEMENTS IN PVR, and CI

LJ Rubin, Chest 2011

Extension study for 259 adult PAH patients Randomized to placebo, 20, 40, 80 mg/tid 71% monotherapy 3 years follow up No benefit of the 80 mg dose over 20 mg dose That was the dose approved after the SUPER 1

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PAP mmHg TA (mmHg)

“ “ “ “SILDENAFIL AMELIORATES EFFECTS OF INHALED NO WITHDRAWAL”. Anesthesiology

1999,91(1):307

cGMP

3 neonates after cardiac surgery 1 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,…

Sildenafil Sildenafil

2005 Increase in 6MWDT Statistically significant Improvement in hemodynamics

16 children Dose 0.5mg/kg to 1mg/kg/dose

36 children 7.5 + 5.9 years Compare iNO and oral sildenafil 0.5 mg/kg through nasogastric tubr In vasoreactivity testing 42% children did not reach detectable level of sildenafil after 0.5 mg/kg oral dose

suboptimal absorption of sildenafil in almost half the children

(J Am Coll Cardiol 2010;55:1456–62) …When detectable, there was no statistically significant 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 hours Nasogastric tube

Small pilot trial PPHN OI> 40, sildenafil (n=7) vs placebo (n=6)

Baquero H et al H Niño Jesus, Barranquilla, Colombia

NO significant systemic hypotension.

2006

36 neonates with PPHN 29 already receiving (iNO). significant improvement in OI after 4 hours of sildenafil infusion in the higher dose cohorts. In 4 neonates, sildenafil was stopped due to adverse events

(28.7 to 19.3; P = .0002) LOADING DOSE:0.4 mg/kg Continuous infusion in 3 HOURS MAINTENANCE : 1.6mg/kg/day Continuous infusion J Pediatrics 2009

2009

84%

83% 4%

Intestinal Neumatosis erectiones

80% Survival at 8 months

2 4 6 8 10 12 14 jun 06 sep 06 feb 09 nov 09

Rpa

AP/AO TPG PVRI initial PVRI

After iNO

June 2006 70% 20 12,59 7 Sept 2006 82% 27 9 8,28 Febr 2009 60% 20 7,8 3,4

Bosentán + ARA II Bosentán + sildenafilo + ARA II Bosentán + sildenafilo + ARA II +iloprost

Trasplante Julio 09

13 year old boy restrictive cardiomyopathy And severe PH AP: BMT por leuKemia

Sildenafil in Heart Trasplant Candidates with high PVR

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ORAL SILDENAFIL ASSOCITED WITH SIGNIFICANT IMPROVEMENT IN RV FUNCTION AND HEMODYNAMICS 23 CHILDREN COMPARED TO OTHER 73 NON TREATED WITH SILDENAFIL

Serdarevic-Pehar and David L. Wessel Alberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski, Hypertension Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Serdarevic-Pehar and David L. Wessel Alberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski, Hypertension Sildenafil 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 old

treatment 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 /SILDENAFIL MONOTHERAPY

Serdarevic-Pehar and David L. Wessel Alberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski, Hypertension Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Serdarevic-Pehar and David L. Wessel Alberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski, Hypertension Sildenafil 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 Consumption cardiorespiratory 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, 2011 http://circ.ahajournals.org/ Downloaded from

Serdarevic-Pehar and David L. Wessel Alberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski, Hypertension Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Serdarevic-Pehar and David L. Wessel Alberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski, Hypertension Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral

Primary “endpoint” was met for medium 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, Hypertension Sildenafil 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, Hypertension Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral

…ALSO DECREASE IN MPAP Y PVRI for the medium and high dose groups EMA Approved sildenafil For pediatric PAH RECOMENDED DOSES CHILDREN <20 Kg: 10 mg/8 horas CHILDREN > de 20 kg: 20 mg/8 horas

Placebo n (%) 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* 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 4 (7)4 (5)8 (5) Pharyngitis 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 4 (7)2 (3)6 (3) Abdominal pain 1 (2)0 3 (6)3 (4)6 (3) Low Medium High Combined n (%) n (%) n (%) n (%)

Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski, Hypertension Sildenafil 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, Hypertension Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral

Dose related

11 serious AEs

2 related to the drug In high dose (80 mg/tid) Ventricular arrythmia and stridor STARTS-2 EXTENSION STUDY END POINTS: SAFETY TOLERABILITY LONG TERM OUTCOMES Increased mortality in the group for children weight > 20 kg , AFTER TWO YEARS OF THERAPY in the high dose group mortality rates 9%, low 14% medium 20% for high Doses groups FDA Drug Safety Communication: FDA recommends against use of Revatio in children with pulmonary hypertension Safety Announcement Additional Information for Patients Additional Information for Healthcare Professionals Data Summary

SILDENAFIL? FDA?

AUGUST 2012

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• “Favorable risk–benefit profile for using low-dose sildenafil in

children with PAH comparable to data from other Registries”.

• “Important differences in baseline () parameters in the high-dose group, including

higher 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 information

regarding 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 SILDENAFIL IN 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 DB

Adressed 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 pediatrics 625 children, More than 140 infants. No REPORTED SAEs in infants 31th March 2014

“The benefit-risk profile of Revatio may be acceptable in individual children…”

MANY CENTERS STARTED CAUTIOUS DOWN TITRATION OF THE DOSES TO 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 REHIPED Sildenafil Dosing And Outcomes : Data from the The Spanish Registry REHIPED

388 pts treated SILDENAFIL

Mean 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)

FONTAN Glenn n=139

PAH n=159 N=90 To be submitted

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UNIVARIATE ANALYSIS MULTIVARIATE ANALYSIS 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

FONTAN Fontan n=139

PAH n=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 RECOMENDATION 10 mg tid < 20 kg 20 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 Dose 8-20 kg < 10 mg tid 10-15 mg tid > 15 mg tid 20-45 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 Dose 8-20 kg NA 10 mg tid 20 mg tid 20-45 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 Medium High 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

Medium Low High P=0.135

SO…. in this retrospective analysis

HIGHER DOSES OF SILDENAFIL WAS NOT AN INDEPENDENT PREDICTOR FOR MORTALITY Our results don´t support a direct relationship between higher doses of sildenafil and worse survival in the pediatric patients included in the Spanish Registry for Pediatric Pulmonary Hypertension.

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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Mono No therapy CCB Dual Triple

Survival in Pediatric PAH

New York/Denver/NL cohort

WM Zijlstra et al 6 J 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 Interaction

Ambrisentan 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

• f 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 children

• btained IN MONOTHERAPY

Risk of insufficient plasma levels due to inadequate absorption…. inadequate compliance…. pharmacokinetic interactions (BOSENTAN)….

SHOULD WE MONITOR PLASMA LEVELS OF 5-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

Event-Free (%) Time (weeks)

0 24 48 72 96 120 144 168 192 TADALAFIL+AMBRISENTA N MONOTHERAPY

Number at risk:

334 pts randomized PACES-2 500 pts ramdomized

Sildenafil 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 sildenafil Sildenafil + bosentan

P=0.107

N= 369 pts PH + Fontan

P=0.41

N= 125 pts PAH (Nice I) sildenafil Sildenafil + bosentan

??? Retrospective Data No Randomization Uni & Multivariate analysis… ??? Retrospective Data No Randomization Uni & Multivariate analysis…

KD Hill et al. Cardiol Young 2016

AUC Hepatic venous pressure (mmHg) 20 Children Single Ventricle Physiology PK after Single IV dose of sildenafil In the cath lab ELEVATED HEPATIC VENOUS PRESSURES DECREASED CLEARANCE OF Des-methyl-sildenafil INCREASING DRUG EXPOSURE “A patient with High venous pressure receiving a Low dose of sildenafil could be having a 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 affected by food or fat meals. Slightly better availability in the morning Near maximal plasma levels from1.5 to 6.5 hours after ingestion Steady state after 10 days of oral intake

ONCE DAiLY administration

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 patients

Treatment naive or on ERA (53%) randomized to placebo/tadalafil Doses from 2.5 mg to 40mg /day

TADALAFIL increased the 6MWDT in a dose dependent manner Only the dose of 40 mg/24 hours Reached the level of statistical significance (p<0.01

40 mg/day

Kaplan–Meier estimates of the proportion of patients with clinical worsening. Galiè N et al. Circulation 2009;119:2894-2903

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

295 completed the 10 months extension study Tadalafil 40 mg improved : time to clinical worsening (p=0.041) Incidence of clinical worsening (68% risk reduction) Health related QOL Common side effects: headache, mialgia, leg pain

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Initial experience with tadalafil in pediatric pulmonary arterial hypertension. Initial experience with tadalafil in pediatric pulmonary 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 sildenafil in catheterized pts (n=14) 6% discontinued tadalafil Due to adverse effects

ONGOING PEDIATRIC CLINICAL TRIALS LVIG LVHV Children < kg: 10 mg Children 20-40 kg: 20 mg Children> 40 kg: 40 mg

tadalafil 1.0 ± 0.4 mg/kg/day

16 ADOLESCENTS /YOUNG ADULTS WITH EISENMNGER SYNDROME

Hemodynamic effect of tadalafil 1 mg/kg up to 40 mg After 90 min (acute effect) after 12 weeks treatment

Improvement in FC and Hemodynamics

2012-2013

18 children PAH in CHD

(14 Eisenmenger syndrome) SILDENAFIL: 54.5 ± 29.3 mg/day (20-100 mg/day) for 4.5 years. Transitioned from sildenafil to tadalafil EVALUATED AFTER 6 WEEKS of tadalafil Iran Improvemnt in 6MWDT

Pediatr Cardiol Nov 2013

increase in Oxygen Sat Similar profile

• f 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)

100 200 300 400 500 600

PRE POST

6MWDT

PDE INHIBITORS : METABOLIC PATHWAY IN PH VASODILATATION and remodelling POSSIBLE ADITIONAL BENEFIT ON RV CONTRACTILITY OF 5PDE inbibitors? SILDENAFIL : WIDESPREAD CLINICAL EXPERIENCE IN ITS USE CONTROVERSY ABOUT THE FDA WARNING Different implications in different countries LESSONS 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 COST than 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 DIFFERENT PART OF THE SAME PATHWAY That 5 PDE inhibitors… THE ACTIVITY OF SILDENAFIL depends 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 Inflammation state Unresposive to endogenos NO and other NO releasing drugs

RATIONALE FOR THE USE OF NO independent activators

• f soluble guanilate ciclase

Rubin et al

Increases in 6MWDT and WHO functional class LONGER TIME TO CLINICAL WORSENING 321 patients Sustained Improvements in 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

• f 0.1–100 l mol/L

Riociguat 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 inducers rifampin, phenytoin, carbamazepine, phenobarbitone SMOKING No clinically relevant pharmacokinetic interactions were discovered with warfarin, aspirin, midazolam, sildenafil. concentration of riociguat

• NITRATES,
• NITRIC OXIDE DONORS
• PHOSFODIESTERASE

INHIBITORS

• PREGNANCY

riociguat concentration

Multicenter, randomized, controlled study 261 patients with unoperable CETPH

• r persistent/recurrent after surgery

Placebo/riociguat for 6 weeks

Primary end point: 6MWDT

Secondary: nt-Pro BNP, PVR, FC Time to clinical worsening

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…Phase III Trials Efficacy 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 tid from Chest- 1 and Patent- 1 (pooled data)

FRACTURE OF PATELLA

3/11/2017 19

Simmoneau Eur Resp J 2014 Rubin et al 324 PAH patients followed after PATENT-1 Dose uo to 2.5 mg t.i.d Increases in 6MWDT and WHO functional class NO EXPERIENCE IN PEDIATRICS CLINICAL TRIAL ONGOING

Rubin et al

Thank you for your attention…

3/11/2017 20

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 1.48 NYHA III 3.2 60 1.99 NYHA IV 4.1 36 2.67 Total 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 patients

treated with SILDENAFIL SILDENAFIL DOSING as potential risk factor for mortality mean dose: 3 mg/kg/day RANGE: 0.5-12 mg/kg/day

233 monotherapy 165 Combination

FONTAN Glenn n=139

PAH n=159 n=90 111 GLENN or FONTAN pts 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

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 weight 20 mg/8 hours children > 20 kg weight 289 PEDIATRIC PATIENTS (PH and Fontan pts) RECEIVING SILDENAFIL HIGHER than EMA recomendatio

according to EMA recomendation

p-valor log-rank ratio = 0.009

FONTAN Glenn n=111

PAH n=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 than EMA recomendation according to EMA recomendation

p-valor log-rank ratio = 0.094

EMA RECOMENDATION: 10 mg/8 hours children < 20 kg weight 20 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 weight 20 mg/8 hours children > 20 kg weight 109 PAH PEDIATRIC PATIENTS RECEIVING SILDENAFIL

HIGHER than EMA recomendation

according to EMA 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 weight 20 mg/8 hours children > 20 kg weight 111 Fontan or Glenn pts RECEIVING SILDENAFIL

FONTAN Glenn n=111

HIGHER than EMA recomendatio

according to EMA 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 bosentan N=15 Bosentan mono N=9 EMA doses

MILRINONE IN PPHN AND POSTOPERATIVE CARE

48 CHILDREN postop shunt closure assigned to: Iv milrinone (n=16) Oral sildenafil (n=16) Combination (n=16)

Milrinone group Lower SPP/SAo P ratio than sildenafil Lower rate in PH crises Lower ICU stay Peiravian F.Iranian J Pediatr 2013

Open label study of milrinone in neonates PPHN and suboptimal response 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 TRIAL

Mc Namara Pediatr Crit Care Med 2013