session 7: therapy update€¦ · (28.7 to19.3; p = .0002) loading dose:0.4 mg/kg...

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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




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







� 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


AFTER 16 WEEKS OF TREATMENT

at Pfizer DIS on December 9, 2011http://circ.ahajournals.org/Downloaded from







Primary “endpoint” was met formedium and high doses

Significant increase in Peak Oxygen Consumption(7.7%) y del 9.5%

2011


AFTER 16 WEEKS

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…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 (%)





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



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




Data From The Spanish Registry For Pediatric PH UNIVARIATE analysis

MULTIVARIATE analysis

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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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…



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



To be submitted


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.





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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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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




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



� 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





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





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





UNIVARIATE analysis

MULTIVARIATE ANALYSIS

HR (95% IC) p-value MPAP 1.23 (1.01-1.50) 0.039





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

3/11/2017

21

178 Pts PHVD (NICE GROUPS I TO V) treated with sildenafil





HIGHER thanEMA recomendation









109 PAH PEDIATRIC PATIENTSRECEIVING SILDENAFIL

HIGHER thanEMA recomendation



P=0.59






111 Fontan or Glenn ptsRECEIVING SILDENAFIL

FONTANGlennn=111

HIGHER thanEMA recomendatio


P=0.44



To be submitted


ALL pts (PH + Fontan)N=388

Low

Medium

High P=0.044

3/11/2017

22

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

session 7: therapy update€¦ · (28.7 to19.3; p = .0002) loading dose:0.4 mg/kg...

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