Treatment of pediatric pulmonary arterial hypertension: A focus on the NO‐sGC‐cGMP pathway

Beghetti, Maurice; Gorenflo, Matthias; Ivy, D. Dunbar; Moledina, Shahin; Bonnet, Damien

doi:10.1002/ppul.24442

Cited by 19 publications

(20 citation statements)

References 107 publications

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“…In adults with CHD the PATENT-1 trial has shown its efficacy in improvement of clinical symptoms, but pediatric experience is limited (81). Current studies aim to clarify the role of riociguat in the treatment of PAH in children (24). After uptitration, the pediatric dose range is 1-2.5 mg t.i.d.…”

Section: Direct Stimulator Of the Soluble Guanylate Cyclasementioning

confidence: 99%

“…Riociguat is under evaluation for treatment in children with PAH (e.g., NCT02562235) (24). Also, Selexipag is currently investigated in pediatric Phase 2 and 3 trials (NCT03492177 and NCT04175600).…”

Section: Ongoing Studiesmentioning

confidence: 99%

“…Up to now, more than 3,000 children worldwide have been included in therapeutic registries, such as PPHnet (North America), TOPP 1 and 2 registry (international) (102), REVEAL pediatric, COMPERA-Kids (international), and the Spanish PAH registry. Through pooling of data across registries and clinical trials, PAH therapy in children should be standardized and optimized (24).…”

Section: Optimal Endpoints For Pediatric Pahmentioning

confidence: 99%

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Treatment of pulmonary arterial hypertension in children

Gorenflo

Ziesenitz

2021

Cardiovasc Diagn Ther

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Pulmonary arterial hypertension (PAH) is a devastating illness causing already significant morbidity in childhood. Currently approved treatment options for children comprise the endothelin receptor antagonist bosentan, as well as the phosphodiesterase-5 inhibitor sildenafil. But PAH treatment has advanced significantly over the past decade, and new classes of targeted drug therapies, such as stimulators of the soluble guanylate cyclase (riociguat) or prostacyclin receptor agonists (selexipag), are currently evaluated regarding their efficacy and safety in children, in order to limit off-label use. Due to the different etiologies in children, such as PAH-CHD, there is no evidence that initial combination therapy in children is superior to a mono-therapy with respect to survival. Special attention should also be paid to the pharmacology of PAH drugs in children, which might be impacted by ontogeny or drug-drug-interactions. Therapeutic drug monitoring may be useful in pediatric patients. There is a clear need for more controlled studies of PAH medications, alone or in combination therapy in the pediatric age group. Data from clinical trials as well as from patient registries should be pooled to optimize drug development and evaluation, trial design, and evidence-based pharmacotherapy in pediatric patients with PAH. In this review, the current treatment options of pediatric PAH are summarized, and an overview of new treatment concepts, which are already evaluated in adults, is presented.

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Section: Direct Stimulator Of the Soluble Guanylate Cyclasementioning

confidence: 99%

Section: Ongoing Studiesmentioning

confidence: 99%

Section: Optimal Endpoints For Pediatric Pahmentioning

confidence: 99%

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Treatment of pulmonary arterial hypertension in children

Gorenflo

Ziesenitz

2021

Cardiovasc Diagn Ther

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“…Riociguat is a first in class sGC stimulator that increases sensitivity of sGC to NO, thus increasing cGMP levels leading to vasorelaxation 84 . It has also been shown to improve clinical outcomes in adults with corrected congenital heart disease 85 .…”

Section: Newer Pah Medicationsmentioning

confidence: 99%

“…In terms of larger studies, based on the encouraging results from the adult PATENT‐1 and 2 studies, the PATENT‐CHILD study is ongoing in pediatric patients aged 6–17 years. Patients will receive doses of adjusted doses of 1–2.5 mg TID or an oral suspension to provide equivalent exposure to adult doses of 0.5–2.5 mg TID 84,87 (NCT02562235).…”

Section: Newer Pah Medicationsmentioning

confidence: 99%

Opportunities and challenges of pharmacotherapy for pulmonary arterial hypertension in children

Kam

Ruiz

2020

Pediatric Pulmonology

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Pediatric pulmonary hypertension (PAH) is a rare disease that carries a poor prognosis if left untreated. Although there are published guidelines for the treatment of children with pulmonary hypertension, due to the limited number of robust pediatric clinical trials, recommendations are often based on limited data or clinical experience. Furthermore, many practical aspects of care, particularly for the pediatric patient, are learned through experience and best navigated with a multidisciplinary team. While newer PAH therapies have been approved for adults, there is still limited but expanding experience in pediatrics. This new information will help improve the targets of goal‐oriented therapy. Lastly, this review highlights practical aspects in the use of the different therapies available for the treatment of pediatric pulmonary hypertension.

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Riociguat in children with pulmonary arterial hypertension: The PATENT–CHILD study

et al. 2022

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Riociguat, a soluble guanylate cyclase stimulator, is approved for treatment of adults with pulmonary arterial hypertension (PAH). The safety, tolerability, and pharmacokinetics (PK) of oral riociguat in a pediatric population with PAH was assessed in PATENT–CHILD (NCT02562235), a multicenter, single‐arm, 24‐week, open‐label, Phase 3 study. Patients aged 6–17 years in World Health Organization functional class (WHO‐FC) I–III treated with stable endothelin receptor antagonists and/or prostacyclin analogs received riociguat equivalent to 0.5–2.5 mg three times daily in adults, as either oral pediatric suspension or tablets, based on bodyweight. Primary outcomes were safety, tolerability, and PK of riociguat. Twenty‐four patients (mean age 12.8 years), 18 of whom were in WHO‐FC II, were enrolled. Adverse events (AEs), mostly mild or moderate, were reported in 20 patients (83%). Four patients (17%) experienced a serious AE; all resolved by study end and two (8%) were considered study‐drug related. Hypotension was reported in three patients and hemoptysis in one (all mild/moderate intensity). Riociguat plasma concentrations in pediatric patients were consistent with those published in adult patients. From baseline to Week 24, mean ± standard deviation increase in 6‐minute walking distance was 23 ± 69 m (n = 19), and mean decrease in NT‐proBNP was –66 ± 585 pg/ml (n = 14). There was no change in WHO‐FC. Two patients experienced clinical worsening events of hospitalization for right heart failure. PK results confirmed a suitable riociguat dosing strategy for pediatric patients with PAH. The data suggest an acceptable safety profile with potential efficacy signals.

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Treatment of pediatric pulmonary arterial hypertension: A focus on the NO‐sGC‐cGMP pathway

Cited by 19 publications

References 107 publications

Treatment of pulmonary arterial hypertension in children

Treatment of pulmonary arterial hypertension in children

Opportunities and challenges of pharmacotherapy for pulmonary arterial hypertension in children

Riociguat in children with pulmonary arterial hypertension: The PATENT–CHILD study

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