3/11/2017 TARGETED TREATMENTS FOR PHVD SESSION 7: Antagonists Prostacyclins Endothelin THERAPY UPDATE Epoprostenol Receptors Treprostinil (ERA) Iloprost BOSENTAN Inhibidores AMBRISENTAN 5-PDE MACITENTAN + Guanilate Sildenafil Dra. Maria Jesús del Cerro Ciclase Tadalafil Pediatric Pulmonary Hypertension Unit Riociguat “RAMON Y CAJAL University Hospital. Madrid, Spain PHOSPHODIESTERASES FOR PHVD Sildenafil Sildenafil � Rapid absorption after oral administration � PDE (1-11) family of (peak plasma levels enzymes Controlling 30 min-2 h hours after cGMP levels. oral administration) � PDE block leads to � Absorption interfered by food, specially fat food. increse in cGMP. � Vasodilatation � Hepatic clearance (cit P450, CYP3A4 , CYP3A7 ): mediatedby Nitric � 5-PDE high concentration interaction with eritromicine, ketoconazol, itrakonazol… Oxide 5- PDE in smooth muscle cells of INHIBITORS the lung vasculature � INTERACTION WITH BOSENTAN (decreases sildenafil exposure up to 50%) Sildenafil Eur J Clin Pharmacol 2008, Br J Clin Pharmacol 2005 � 5-PDE highly expressed in Tadalafil human hypertrohied RV Vardenafil � Half life. 4 hours ORAL ADMINISTRATION inhibition of 5PDE improve EVERY 6-8 HOURS RV contractility Phosphodiesterase Type 5 Is Highly Expressed in the Hypertrophied Human Right Ventricle, and Acute Inhibition � Inter-ethnic variability in PK: Sildenafil exposure much higher in of Phosphodiesterase Type 5 Improves. Contractility. (Circulation. 2007;116:238-248.) Mexican subjects compared to Caucasians ( Flores-Murrieta, 2000 ) Sildenafil treatment in stablished RV failure improves s diastolic function and attenuates interstotial fibrosis. Circ Physiol 207; H361-369. 2014 1
3/11/2017 278 adults pts 12 weeks trial SILDENAFIL vs placebo Randomised, controlled trial IMPROVEMENTS IN 6MWDT IMPROVEMENTS IN PVR, and CI 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 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 LJ Rubin, Chest 2011 2
3/11/2017 Sildenafil Sildenafil “ “ “ “ SILDENAFIL FIRST REPORTED USE IN PEDIATRICS in 1999… AMELIORATES WITHDRAWAL ” . EFFECTS OF TA (mmHg) INHALED NO cGMP Anesthesiology 1999, 91(1):307 PAP mmHg 3 neonates after cardiac surgery 1 mg por SNG FOLLOWED BY widespread off-label use of the drug…. CASE REPORTS , CONTROLLED, NON RANDOMISED… SMALL TRIALS, mostly in IPAH, CHD-PAH, postoperative,… 2005 36 children 7.5 + 5.9 years 16 children Compare iNO and oral sildenafil Dose 0.5mg/kg to 1mg/kg/dose 0.5 mg/kg through nasogastric tubr In vasoreactivity testing …When detectable, there was no statistically significant difference between the fall in PVRI associated with sildenafil and … 42% children did not reach detectable level of sildenafil Increase in 6MWDT after 0.5 mg/kg oral dose suboptimal absorption of sildenafil Statistically significant in almost half the children Improvement in hemodynamics (J Am Coll Cardiol 2010;55:1456–62) 3
3/11/2017 2006 Baquero H et al H Niño Jesus, Barranquilla, Colombia 1-2 mg/kg/6 hours Small pilot trial PPHN OI> 40, Nasogastric tube sildenafil (n=7) vs placebo (n=6) 2009 36 neonates with PPHN 29 already receiving (iNO). significant improvement in OI after 4 hours of sildenafil infusion in the higher dose cohorts. (28.7 to 19.3; P = .0002) In 4 neonates , sildenafil was stopped due to adverse events LOADING DOSE:0.4 mg/kg Oral sildenafil produced NO significant systemic Continuous infusion significant changes in OI. hypotension. in 3 HOURS MAINTENANCE : 1.6mg/kg/day Continuous infusion Baquero H et al. Pediatrics 2006;117:1077- J Pediatrics 2009 Sildenafil in Heart Trasplant 80% Survival at 8 months Candidates with high PVR Rpa 14 Bosentán + ARA II 84% 12 Bosentán + AP/AO TPG PVRI PVRI 10 sildenafilo + ARA II After iNO initial Bosentán + sildenafilo 8 June 70% 20 12,59 7 + ARA II +iloprost 2006 6 Sept 82% 27 9 8,28 2006 4 Trasplante Intestinal Neumatosis Febr 60% 20 7,8 3,4 Julio 09 erectiones 2 4% 2009 83% 0 13 year old boy restrictive cardiomyopathy And severe PH jun 06 sep 06 feb 09 nov 09 AP: BMT por leuKemia 4
3/11/2017 A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial Hypertension Hypertension Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski, Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski, Alberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana Alberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana Serdarevic-Pehar and David L. Wessel Serdarevic-Pehar and David L. Wessel 234 PAH children 1-17 years old treatment naïve ORAL SILDENAFIL ASSOCITED WITH Etiology SIGNIFICANT IPAH/HPAH (33%) IMPROVEMENT APAH (67%) IN RV FUNCTION PAH after Surgical repair † (52) AND HEMODYNAMICS Congenital systemic-to-pulmonary shunt with SaO 2 ≥88% at rest (62) 23 CHILDREN COMPARED Postrepair D-transposition of great arteries (3) TO OTHER 73 NON TREATED WITH SILDENAFIL RANDOMISED TO PLACEBO /SILDENAFIL MONOTHERAPY Barst R J et al. Circulation 2012;125:324-334 A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial Hypertension Hypertension Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial Hypertension Hypertension Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski, Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski, Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski, Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski, Alberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana Alberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana Alberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana Alberto E. Garcia, B. K. S. Sastry, Tomas Pulido, Gary R. Layton, Marjana Serdarevic-Pehar and David L. Wessel Serdarevic-Pehar and David L. Wessel Serdarevic-Pehar and David L. Wessel Serdarevic-Pehar and David L. Wessel 2012 2011 Body Weight, kg Sildenafil Dose, mg AFTER 16 WEEKS EFFICACY Primary “endpoint” � Primary “endpoint”: Low Medium High was met for Changes in EXERCISE CAPACITY medium and high doses NA † 10 † Peak Oxygen Consumption ≥8 to 20 20 >20 to 45 10 20 40 cardiorespiratory testing Significant increase in >45 10 40 80 Peak Oxygen Consumption (7.7%) y del 9.5% � Secondary “endpoints”: Changes in MPAP, PVRI, CI, AFTER 16 WEEKS OF TREATMENT Functional Class Downloaded from http://circ.ahajournals.org/ at Pfizer DIS on December 9, 2011 Barst R J et al. Circulation 2012;125:324-334 Barst R J et al. Circulation 2012;125:324-334 5
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