Disclosure NO-cGMP Agonists and Phosphodiesterase-5 Inhibitors no - PowerPoint PPT Presentation

4/21/2018 Disclosure NO-cGMP Agonists and Phosphodiesterase-5 Inhibitors no financial disclosures A Bates, MD, FRCPC Edmonton, AB CANADA Stollery Children’s Hospital all drugs are off-label for use in children at this time* 11th International Conference Neonatal & Childhood Pulmonary Vascular Disease Objectives overview of mechanism of action historical evidence what is available for pediatric patients? old, new, future… Humbert M et al. Circulation. 2014;130 1

4/21/2018 endogenous pulmonary vasodilator endothelial-derived relaxing factor (EDRF) synthesized from L-arginine by NO synthase dysfunction in the NO pathway plays a key role in progress of PH disease Tang et al. Pulmonary Circulation 2017 Action of cGMP The correlation of plasma cGMP levels with PAP has been demonstrated in promotes smooth muscle relaxation hypoxic mice cGMP activates protein kinase G → K channels on the sarcolemma → intracellular hyper polarization → inhibition of voltage-gated Ca channels → vasorelaxation inhibits smooth muscle proliferation, leucocyte The metabolism of cGMP is mediated primarily recruitment, inflammation, fibrosis, platelet aggregation PDE5, which is expressed in high concentrations in ? pulmonary vascular remodelling lung tissue Am J Respir Crit Care Med. 2008 Biochem Biophys Res Commun 2005 2

4/21/2018 Sildenafil - REVATIO phosphodiesterase-5 inhibitor most well know for vasodilatory effects in erectile dysfunction SILDENAFIL goal: accumulation of cGMP a series of cellular changes with a decrease in intracellular Ca levels, relaxation of smooth muscles improved RV function and reduced smooth muscle cell proliferation Simonca and Tulloh Children 2017 Sildenafil STARTS-1 trial well studied in adult pulmonary hypertension and approved 2005 235 treatment naïve children (1-17y) with IPAH or APAH-CHD SUPER-1,2 - RCT : improve exercise capacity, functional status, and hemodynamics randomized, placebo-controlled trial of 3 doses (low, medium, high) vs. placebo given for 16 wks Indicated for the treatment of PAH (Group I) in adults to improve exercise ability and delay clinical Primary endpoint : percent change in peak oxygen worsening consumption for combined doses from baseline landmark trials for children > 12yrs old (STARTS-1, 2) Exercise testing performed in 115 children Barst RJ, et al. Circ, 2012 3

4/21/2018 Dose-Related Late Mortality in STARTS trials the Pediatric Sildenafil Study STARTS-1 results: STARTS-2 results: Primary endpoint marginally significant in combined dosages ongoing long-term 2 yr extension to STARTS-1 study Primary endpoint significant in medium and high doses Increased mortality in high dose group, esp > 20 kg and IPAH/HPAH Improvements in functional class and hemodynamics in medium and high doses FDA warning against use of sildenafil in children 1-17 years as a result Barst RJ, et al. Circ, 2012 The FDA warning states that “this recommendation against [Sildenafil] use is based on a recent long-term clinical pediatric trial showing that: (1) children taking a high dose of Revatio had a higher BLACK BOX WARNING! risk of death than children taking a low dose (2) the low doses of Revatio are not effective in improving exercise ability Revatio has never been approved for the treatment of PAH in children, and in light of the new clinical trial information, off-label (not approved by FDA) use of the drug in pediatric patients is not recommended.” 4

4/21/2018 PPHnet statement Oral Sildenafil clinical improvement in exercise capacity was PO Sildenafil - 0.5 to 1.5 h absorption, 40% bioavailability observed at 12 months during the study extension period for combined study doses liver first pass metabolism; fecal and renal clearance half life of 2-4 hours survival was 91% at 3 years with low-dose Sildenafil monotherapy in treatment-naive children with Age & Weight: significant PAH <1 y: 0.5–1 mg/kg 3 times daily orally overall, the data show a favorable risk/benefit profile for using low-dose Sildenafil in children 10 kg - 20 kg - 10 mg PO q8h with PAH that is comparable to data from other patient registries > 20 kg - 20 mg PO q8h IV Sildenafil Sildenafil IV Sildenafil - use 10 mg/12.5 mL; ~40% bioavailable Side Effects: 0.5 mg/kg/dose q8h systemic hypotension epistaxis, flushing, headaches, GI intolerance continuous infusion equivalent of 60 mcg/kg/hr * upper respiratory tract symptoms (nasal congestion, not available in all countries, limited evidence in cough) critical care, neonatology and cardiac cath lab priapism used effectively in postoperative PH peripheral edema, myalgia CONCLUSION: reduced PAP and shortened time to extubation and ICU LOS dizziness, visual disturbances, hearing loss Fraisse, A et al Intensive Care Med 2011 5

4/21/2018 Sildenafil Contraindications: severe hypotension, left sided heart obstruction/PVS* ? ischemic optic neuropathy and hereditary degenerative retinal disorders delay use in extremely preterm infants until retinal vascularization is established Co-administration of Bosentan leads to decreased Sildenafil concentrations and increased Bosentan concentrations avoid nitrates Sildenafil Sildenafil Indications in children Incidence of vascular, GI, and neurologic SE in pediatric patients on Sildenafil therapy for PAH was 30% European Society of Cardiology (ESC) recommend Sildenafil therapy in children, for those aged 1–17 SE were more common in patients on combo therapy years old with PAH vs. monotherapy avoid rebound PH weaning off iNO (esp Post op PAH) Neonates: PPHN, BPD, CDH Perez & Laughorn (Clinical Therapeutics 2015) - no evidence for prevention of BPD; no studies looking at prevention of PH with Sildenafil Ladha et al., 2005; De Visser et al., 2009 Siehr et al . Frontiers in Paediatrics 2015. 6

4/21/2018 Tadalafil - ADCIRCA highly selective for the PDE-5 isozyme in humans longer acting than Sildenafil TADALAFIL landmark trials in adults only ( PHIRST-1, 2 ); approved in 2009 Indicated for the treatment of pulmonary arterial hypertension (WHO Group I) to improve exercise ability Takatsuki S et al Pediatr Cardiol. 2012 Tadalafil Tadalafil No Approved indications in Peds time to peak effect: 75-90 minutes; half life 17.5 hours evaluated only in children >3 y of age adjust in renal dysfunction experience with compounded suspensions in young Dosing: infants Starting dose: 0.5-1 mg/kg/d safe and effective Optimal dose: 1mg/kg/day once daily PO to max of Improved outcome in patients with combination 40 mg PO OD therapy? (AMBITION trial) less interaction with Ambrisentan vs. Bosentan Gail N et al. NEJM 2015 Yamasaki H et al. Current Medical Research and Opinion. 2017 Takatsuki S et al Pediatr Cardiol. 2012 7

4/21/2018 Tadalafil Tadalafil 2017 - sub-group analysis of 391 pediatric PAH pts (<18y) ADRs incidence - 16.6% Side effects: 16 SADRs - 3 pts died (cardiac failure) similar to Sildenafil; most common = headache incidence of WHO functional class improvement at 3 mo, less likely to cause hypotension (unless 1 y, and 2 y after Tadalafil were 16.5%, 19.7%, and coadministered with other vasodilating drugs) 16.3% thrombocytopenia, platelet dysfunction both PAP and TRPG showed a statistically significant reduction Yamasaki H et al. Current Medical Research and Opinion. 2017 Tadalafil Sildenafil to Tadalafil Retrospective pediatric review of 29 patients 125 patients discontinued Tadalafil (~1/3) transitioned reasons for discontinuation were improvement of main reason: once daily dosing PAH condition (50), AE (32), change to another Rx (14), no visit (2), insufficient effect (1), other (25), avg dose of Sildenafil (3.4 +/− 1.1 mg/kg/d) & Tadalafil and undescribed (1) (1.0 +/− 0.4 mg/kg/d) common AEs that resulted in discontinuation were PH 14/29 patients had statistically significant (aggravation of primary disease), abnormal hepatic improvements in mPAP and PVRi function, myalgia, vomiting, multi-organ failure, and pleural effusion 4 had clinical improvement; similar side effects Yamasaki H et al. Current Medical Research and Opinion. 2017 Takatsuki S et al Pediatr Cardiol. 2012 8

4/21/2018 Riociguat Riociguat has a dual mode of action RIOCIGUAT 1) synergistic with endogenous NO by sensitizing sGC 2) directly stimulates sGC independently of NO to increase the generation of cGMP efficacy in combination therapy with ERAs Expert Opin. Pharmacother. 2014 Riociguat Riociguat Adult Trials approved for the treatment in adults for PAH and inoperable or recurrent chronic thromboembolic PH Soluble GC is expressed in vascular smooth muscle (CTEPH) cells of pulmonary vessels , platelets, cardiomyocytes, etc. phase III trials are multi-center studies it catalyzes the conversion of guanosine triphosphate randomized, double-blind, placebo-controlled pivotal trial (GTP) to cGMP phase ( CHEST-1 & PATENT-1 ) open label extension trial phase ( CHEST-2 & PATENT-2 ) Ghofrani HA et al. NEJM 2013 Rubin L et al. Eur Respir J 2015 Gail N et al. J Heart Lung Transplant 2017 9