TARGETED TREATMENTS FOR PHVD SESSION 7: THERAPY UPDATE

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1 TARGETED TREATMENTS FOR PHVD SESSION 7: THERAPY UPDATE Antagonists Endothelin Receptors (ERA) Prostacyclins Epoprostenol Treprostinil Iloprost Dra. Maria Jesús del Cerro Pediatric Pulmonary Hypertension Unit RAMON Y CAJAL University Hospital. Madrid, Spain BOSENTAN AMBRISENTAN MACITENTAN + Guanilate Ciclase Riociguat Inhibidores 5-PDE Sildenafil Tadalafil PHOSPHODIESTERASES FOR PHVD 5-PDE high concentration in smooth muscle cells of the lung vasculature 5-PDE highly expressed in human hypertrohied RV inhibition of 5PDE improve RV contractility 5- PDE INHIBITORS Sildenafil Tadalafil Vardenafil 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 of Phosphodiesterase Type 5 Improves. Contractility. (Circulation. 2007;116: ) Sildenafil treatment in stablished RV failure improves s diastolic function and attenuates interstotial fibrosis. Circ Physiol 207; H 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 Rapid absorption after oral administration (peak plasma levels 30 min-2 h hours after oral administration) ORAL ADMINISTRATION EVERY 6-8 HOURS Inter-ethnic variability in PK: Sildenafil exposure much higher in Mexican subjects compared to Caucasians (Flores-Murrieta, 2000) 1

2 278 adults pts 12 weeks trial SILDENAFIL vs placebo Randomised, controlled trial IMPROVEMENTS IN PVR, and CI IMPROVEMENTS IN 6MWDT 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

3 Sildenafil FIRST REPORTED USE IN PEDIATRICS in 1999 TA (mmhg) cgmp PAP mmhg SILDENAFIL AMELIORATES EFFECTS OF INHALED NO WITHDRAWAL. Anesthesiology 1999,91(1):307 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, children Dose 0.5mg/kg to 1mg/kg/dose Increase in 6MWDT Statistically significant Improvement in hemodynamics 36 children years Compare ino and oral sildenafil 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 after 0.5 mg/kg oral dose suboptimal absorption of sildenafil in almost half the children (J Am Coll Cardiol 2010;55: ) 3

4 Baquero H et al H Niño Jesus, Barranquilla, Colombia 2006 Small pilot trial PPHN OI> 40, sildenafil (n=7) vs placebo (n=6) 1-2 mg/kg/6 hours Nasogastric tube 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 Oral sildenafil produced significant changes in OI. NO significant systemic hypotension. LOADING DOSE:0.4 mg/kg Continuous infusion in 3 HOURS Baquero H et al. Pediatrics 2006;117:1077- J Pediatrics 2009 MAINTENANCE : 1.6mg/kg/day Continuous infusion 80% Survival at 8 months Sildenafil in Heart Trasplant Candidates with high PVR 84% 4% 83% Intestinal Neumatosis erectiones June 2006 Sept 2006 Febr 2009 AP/AO TPG PVRI initial PVRI After ino 70% 20 12, % ,28 60% 20 7,8 3,4 13 year old boy restrictive cardiomyopathy And severe PH AP: BMT por leukemia Bosentán + ARA II Bosentán + sildenafilo + ARA II Rpa Bosentán + sildenafilo + ARA II +iloprost Trasplante Julio 09 jun 06 sep 06 feb 09 nov 09 4

5 A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial Hypertension 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 Serdarevic-Pehar and David L. Wessel ORAL SILDENAFIL ASSOCITED WITH SIGNIFICANT IMPROVEMENT IN RV FUNCTION AND HEMODYNAMICS 23 CHILDREN COMPARED TO OTHER 73 NON TREATED WITH SILDENAFIL 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 SaO 2 88% at rest (62) Postrepair D-transposition of great arteries (3) RANDOMISED TO PLACEBO /SILDENAFIL MONOTHERAPY Barst R J et al. Circulation 2012;125: A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial Hypertension 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 Serdarevic-Pehar and David L. Wessel 2012 A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial Hypertension 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 Serdarevic-Pehar and David L. Wessel 2011 Body Weight, kg Sildenafil Dose, mg Low Medium High 8 to 20 NA >20 to > AFTER 16 WEEKS OF TREATMENT EFFICACY Primary endpoint : Changes in EXERCISE CAPACITY Peak Oxygen Consumption cardiorespiratory testing Secondary endpoints : Changes in MPAP, PVRI, CI, Functional Class AFTER 16 WEEKS Primary endpoint was met for medium and high doses Significant increase in Peak Oxygen Consumption (7.7%) y del 9.5% Barst R J et al. Circulation 2012;125: Downloaded from at Pfizer DIS on December 9, 2011 Barst R J et al. Circulation 2012;125:

6 A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial Hypertension A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial Hypertension EMA Approved sildenafil For pediatric PAH RECOMENDED DOSES CHILDREN <20 Kg: 10 mg/8 horas CHILDREN > de 20 kg: 20 mg/8 horas ALSO DECREASE IN MPAP Y PVRI for the medium and high dose groups Barst R J et al. Circulation 2012;125: 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 * (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 (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 (7) 2 (3) 6 (3) Abdominal pain 1 (2) 0 3 (6) 3 (4) 6 (3) Low Medium High Combined n (%) n (%) n (%) n (%) Dose related STARTS-2 EXTENSION STUDY END POINTS: SAFETY TOLERABILITY LONG TERM OUTCOMES 11 serious AEs 2 related to the drug In high dose (80 mg/tid) Ventricular arrythmia and stridor 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 FDA? AUGUST 2012 SILDENAFIL? mortality rates 9%, low 14% medium 20% for high Doses groups Increased mortality in the group for children weight > 20 kg, AFTER TWO YEARS OF THERAPY in the high dose group 6

7 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 PPHNET RECOMMENDATIONS 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. 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 SILDENAFIL MONOTHERAPY IS LIKELY INSUFFICIENT WITH DISEASE PROGRESSION Am J Crit Care Med 2013 Adressed the caveats of Super study: Mc Elhinney DB 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.. Circulation. 2014; 129:

8 Al Dodgen 31th March 2014 Review of 49 reports on sildenafil use in pediatrics 625 children, More than 140 infants. No REPORTED SAEs in infants The benefit-risk profile of Revatio may be acceptable in individual children : Data from the The Spanish Registry REHIPED 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 To be submitted 233 monotherapy 388 pts treated SILDENAFIL Mean Follow Up y (range 0-12 y) mean dose: 3 mg/kg/day RANGE: mg/kg/day 165 Combination ANALIZED SURVIVAL AND MORTALITY RISK FACTORS FOR : Etiology (NICE groups I to V) FONTAN N=90 Glenn n=139 PAH n=159 All PH pts (n=249) PAH pts (n= 159) Fontan pts (n=139) PH + FONTAN (n=388) Age at diagnosis FC at diagnosis Right atrial pressure mpap, cardiac index (CI), PVRI, sildenafil dosing (0.5mg/kg/day increase) Combined treatment 8

9 In Pediatric Pulmonary Hypertension: N=90 PAH n=159 FONTAN Fontan n=139 UNIVARIATE ANALYSIS 249 Pts PHVD (NICE GROUPS I TO V) UNIVARIATE analysis MULTIVARIATE ANALYSIS MULTIVARIATE To be submitted To be submitted In Pediatric Pulmonary Hypertension: 159 PAH Pts (NICE GROUP I ) treated with sildenafil UNIVARIATE analysis MULTIVARIATE analysis All pts Ph +Fontan (n=388) PH Nice I to V (n=249) EMA RECOMENDATION 10 mg tid < 20 kg 20 mg/tid > 20 kg PAH Nice I (n=159) Fontan I (n=139) To be submitted 9

10 Classifying REHIPED patients according to the STARTS trial dosing Classifying our patients according to the Starts trial dosing Dose interval Low dose Medium Dose High Dose 8-20 kg < 10 mg tid mg tid > 15 mg tid kg < 15 mg tid mg tid > 30 mg tid > 45 kg < 15 mg tid mg tid > 60 mg tid STARTS trial dosing Dose interval Low dose Medium Dose High Dose 8-20 kg NA 10 mg tid 20 mg tid kg 10 mg tid 120 mg tid 40 mg tid > 45 kg 10 mg tid 40 mg tid 80 mg tid Medium High Low P=0.044 Medium High Low P=0.34 To be submitted ALL pts (PH + Fontan) N=388 PH Nice I to V + Fontan) N=249 To be submitted Classifying our patients according to the Starts trial dosing Medium Low High P=0.135 In Pediatric Pulmonary Hypertension: 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. PAH Nice I N= 98 To be submitted 10

11 Survival in Pediatric PAH New York/Denver/NL cohort Pharmacokinetic Interactions Between PAH-specific Medications WM Zijlstra et al 6 J Am Coll Cardiol 2014;63: Sitbon O et al, Eur resp J 2016 CCB Triple Dual Mono No therapy 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 of systemic hypotension Epoprostenol None N/A Iloprost None N/A Treprostinil None N/A FDA. Package inserts for above products. Accessed at scripts/cder/drugsatfda/index.cfm?fuseaction=search.search_drug_name. Accessed December 15, Pharmacokinetic data on children obtained IN MONOTHERAPY SILDENAFILO AND BOSENTAN.. Most common oral combination therapy in pediatrics. IS THE PHARMACOKINETIC INTERACTION CLINICALLY RELEVANT? Risk of insufficient plasma levels due to inadequate absorption. inadequate compliance. pharmacokinetic interactions (BOSENTAN). 50 KG WEIGHT 13 YEARS OLD CHILD RECEIVING 20 mg/8 hours + BOSENTAN 125 mg/12 h DOES HE HAVE ADEQUATE SILDENAFIL LEVELS??? SHOULD WE MONITOR PLASMA LEVELS OF 5-PDE INHIBITORS SPECIALLY WHEN USED IN COMBINATION WITH BOSENTAN? Hakamata A, et al. Sild+bos Sild+ambrisentan 11

12 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 SILDENAFILO AND BOSENTAN.. Most common oral combination therapy in pediatrics. IS THE PHARMACOKINETIC INTERACTION CLINICALLY RELEVANT? Event-Free (%) MONOTHERAPY TADALAFIL+AMBRISENTA N 500 pts ramdomized Time Number at risk: (weeks) PACES pts randomized Sild +Bosentan Sildenafil Sildenafil + bosentan P=0.107 sildenafil N= 369 pts PH + Fontan sildenafil Sildenafil + bosentan??? Retrospective Data P=0.41 No Randomization Uni & Multivariate analysis N= 125 pts PAH (Nice I) To be submitted 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 Yokohama Y et al. 50 microlitres of blood AUC Hepatic venous pressure (mmhg) A patient with High venous pressure receiving a Low dose of sildenafil could be having a HIGH EXPOSURE EQUIVALENT TO RECEIVING A HIGH DOSE Optimize dosing for individual pts Evaluate Interactions in Combination Therapy KD Hill et al. Cardiol Young

13 PHARMACOKINETICS REPORTED EXPERIENCE IN PAH ADULTS REPORTED TADALAFIL EXPERIENCE IN PHVD IN CHILDREN Forgue ST. Br J Clin Pharmacol 2006, 61(3): Linear correlationship between dose and plasma levels (dose proportionality) Half life 17 hours. Absorption NO affected by food or fat meals. ONCE DAiLY administration 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 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 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< mg/day Circulation 2009, 119(22): 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 GalièN et al. Circulation 2009;119: Kaplan Meier estimates of the proportion of patients with clinical worsening. Common side effects: headache, mialgia, leg pain 13

14 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, tadalafil 1.0 ± 0.4 mg/kg/day Children < kg: 10 mg Children kg: 20 mg Children> 40 kg: 40 mg 6% discontinued tadalafil Due to adverse effects 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 ONGOING PEDIATRIC CLINICAL TRIALS LVIG LVHV Improvement in FC, MPAP and PVRI, PVRI/SVRI compared to sildenafil in catheterized pts (n=14) Pediatr Cardiol Jun;33(5): Iran children PAH in CHD (14 Eisenmenger syndrome) SILDENAFIL: 54.5 ± 29.3 mg/day ( mg/day) for 4.5 years. Transitioned from sildenafil to tadalafil EVALUATED AFTER 6 WEEKS of tadalafil increase in Oxygen Sat Similar profile of side effects Improvemnt in 6MWDT 34 pts: Experience TADALAFIL Ramón y Cajal University Hospital 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%). Pediatr Cardiol Nov

15 Diagnosis: Experience TADALAFIL Ramón y Cajal University Hospital -10 (28,6%) Corrected CHD Experience TADALAFIL Ramón y Cajal University Hospital Increase in 6MWDT from 441 to MWDT -12 (34,3%) Eisenmenger IMPROVED COMPLIANCE in all (2,9%) Fontan -4 PH Lung disease (3 BPD) AES: Only 1 pt interrupted treatment (increased menstrual bleeding) PRE POST - 7 (20%) HAPI 1 pt needed decrease in dose (headache) 1 pt slower titration (leg pain) 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!!!! 15

16 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 RATIONALE FOR THE USE OF NO independent activators of soluble guanilate ciclase 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 Inflammation state Altered redox state of sgc Unresposive to endogenos NO and other NO releasing drugs 321 patients Sustained Improvements in 6MWDT Increases in 6MWDT and WHO functional class LONGER TIME TO CLINICAL WORSENING NO EXPERIENCE IN PEDIATRICS CLINICAL TRIAL ONGOING Rubin et al 16

17 RIOCIGUAT DEVELOPMENT Eur Respir J. 2008;32(4): In vitro concentrations of l mol/l Riociguat stimulated recombinant rat sgc, with a 2- to 73-fold increase in activity from basal levels From animal models REDUCING RV HYPERTROPHY and Muscularization of peripheral arteries in rats monocrotaline model of PH J Clin Pharmacol. 2008;48(8): TO PHASE I: safety, Pharmacokinetic & pharmacodynamic studies in healthy volunteers 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 Eur Respir J. 2009;33(4): TO PHASE II STUDIES in PAH and CTEPH Rapid absorption, minimally interfered by food. Maximum plasma concentration (Cmax ) in h Pharmacokinetics linear and dose proportional High absolute bioavailability 94 %. Hepatic & lung metabolism to less active metabolites Half-life : 7-12 hours Multicenter, randomized, controlled study 261 patients with unoperable CETPH or persistent/recurrent after surgery CYP and P-glycoprotein/BCRP inhibitors: ketoconazole/itraconazole,ritonavir, CyA) CYP3A4 inducers rifampin, phenytoin, carbamazepine, phenobarbitone SMOKING riociguat concentration concentration of riociguat No clinically relevant pharmacokinetic interactions were discovered with warfarin, aspirin, midazolam, sildenafil. NITRATES, NITRIC OXIDE DONORS PHOSFODIESTERASE INHIBITORS PREGNANCY Placebo/riociguat for 6 weeks Primary end point: 6MWDT Secondary: nt-pro BNP, PVR, FC Time to clinical worsening 17

18 Phase III Trials Efficacy of Riociguat tested in N= 261 patients CHANGE IN FUNCTIONAL CLASS 0.5 to 2. 5 mg t.i.d Tolerability of riociguat mg tid from Chest- 1 and Patent- 1 (pooled data) CTEPH PAH Ghofrani HA, et al Ghofrani HA, et al FRACTURE OF PATELLA 18

19 NO EXPERIENCE IN PEDIATRICS CLINICAL TRIAL ONGOING 324 PAH patients followed after PATENT-1 Dose uo to 2.5 mg t.i.d Increases in 6MWDT and WHO functional class Simmoneau Eur Resp J 2014 Rubin et al Rubin et al Thank you for your attention 19

20 In Pediatric Pulmonary Hypertension: In Pediatric Pulmonary Hypertension: < 3mg/kg/day < 3-4mg/kg/day > 4mg/kg/day 249 Pts PHVD (NICE GROUPS I TO V) treated with sildenafil SILDENAFIL DOSING as potential risk factor for mortality 233 monotherapy 388 patients treated with SILDENAFIL mean dose: 3 mg/kg/day RANGE: mg/kg/day 165 Combination NYHA FC MEAN SILDENAFIL DOSE mg/k/day n SD NYHA I-II NYHA III NYHA IV Total n pts FONTAN n=90 Glenn n=139 PAH n=159 In Pediatric Pulmonary Hypertension: In Pediatric Pulmonary Hypertension: 111 GLENN or FONTAN pts treated with sildenafil UNIVARIATE analysis 289 PEDIATRIC PATIENTS (PH and Fontan pts) RECEIVING SILDENAFIL EMA RECOMENDATION: 10 mg/8 hours children < 20 kg weight 20 mg/8 hours children > 20 kg weight n=61 FONTAN Glenn n=111 HIGHER than EMA recomendatio MULTIVARIATE ANALYSIS PAH n=109 HR (95% IC) p-value MPAP 1.23 ( ) according to EMA recomendation p-valor log-rank ratio =

21 In Pediatric Pulmonary Hypertension: In Pediatric Pulmonary Hypertension: 178 Pts PHVD (NICE GROUPS I TO V) treated with sildenafil EMA RECOMENDATION: 10 mg/8 hours children < 20 kg weight 20 mg/8 hours children > 20 kg weight 109 PAH PEDIATRIC PATIENTS RECEIVING SILDENAFIL EMA RECOMENDATION: 10 mg/8 hours children < 20 kg weight 20 mg/8 hours children > 20 kg weight HIGHER than EMA recomendation HIGHER than EMA recomendation P=0.59 according to EMA recomendation p-valor log-rank ratio = according to EMA recomendation p-valor log-rank ratio = In Pediatric Pulmonary Hypertension: 111 Fontan or Glenn pts RECEIVING SILDENAFIL FONTAN Glenn n=111 EMA RECOMENDATION: 10 mg/8 hours children < 20 kg weight 20 mg/8 hours children > 20 kg weight according to EMA recomendation HIGHER than EMA recomendatio P=0.44 Classifying our patients according to the Starts trial dosing Low Medium High P=0.044 ALL pts (PH + Fontan) N=388 To be submitted 21

22 EMA doses Sild add to bosentan N=15 Bosentan mono N=9 MILRINONE IN PPHN AND POSTOPERATIVE CARE Douwes JM et al. Heart 2014 Milrinone group Lower SPP/SAo P ratio than sildenafil 48 CHILDREN postop shunt closure assigned to: Iv milrinone (n=16) Oral sildenafil (n=16) Combination (n=16) Lower rate in PH crises Lower ICU stay 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 ( μg/kg/min) for hrs Peiravian F.Iranian J Pediatr 2013 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