Oral drugs used to treat persistent pulmonary hypertension of the newborn

ABSTRACT

Introduction:Persistent Pulmonary Hypertension of the Newborn (PPHN) is a life-threatening neonatal condition, mostly treated with inhaled nitric oxide (iNO), intravenous prostaglandins, oral bosentan, sildenafil and tadalafil. However, the utility of non-oral agents is limited in PPHN for their side effects and inconvenient deliveries. Therefore, oral agents such as bosentan, sildenafil and tadalafil are becoming appealing for their satisfactory efficacy, easy mode of administration and acceptable side effects.

Areas covered: We conducted a comprehensive search on Pubmed, Scopus, Web of Sciences concerning the use of bosentan, sildenafil and tadalafil to treat PPHN and summarized their efficacy, safety and pharmacokinetics.

Expert opinion: Current randomized controlled trials (RCTs) have demonstrated the favorable responses and tolerable side effects of bosentan and sildenafil. Nevertheless, those RCTs are small and only one study has described the pharmacokinetics of sildenafil in neonates. Accordingly, bosentan, sildenafil and tadalafil remain off-label in clinical use. More well-designed RCTs with large samples and long-term follow-up and pharmacometrics studies are needed to demonstrate the efficacy, safety and pharmacokinetics of bosentan, sildenafil and tadalafil in PPHN.

KEYWORDS:

• Bosentan
• tadalafil
• efficacy
• persistent pulmonary hypertension of the newborn pharmacokinetics
• safety
• sildenafil

Article highlights

• PPHN is a life-threatening neonatal condition with a higher mortality rate in developing countries, resulting from insufficient modern resources, such as iNO, high-frequency oscillatory ventilation (HFOV), and extracorporeal membrane oxygenation (ECMO).

• Although used off-label, oral bosentan, sildenafil and tadalafil have shown favorable efficacy and acceptable tolerance in neonates with PPHN.

• 36 papers have demonstrated the clinical studies of bosentan (3 case reports, 1 retrospective study, 2 RCTs), sildenafil (13 case reports, 4 retrospective studies, 6 prospective studies, 6 RCTs) and tadalafil (1 prospective study).

• Efficacy outcomes, including oxygenation index (OI) and pulmonary arterial pressure (PAP), show significant improvement during treatment with bosentan, sildenafil or tadalafil.

• The most frequent adverse effect of bosentan and sildenafil is hypotension, whereas there are no reported side effects of the use of tadalafil because of its limited use so far.

• The oral absorption of bosentan, sildenafil and tadalafil is rapid. Their metabolism takes place in the liver, and they are primarily excreted by the biliary system into the feces.

• Population pharmacokinetics of bosentan and tadalafil in PPHN is not available. Only one study has documented the pharmacokinetics of sildenafil in neonates.

• Well-designed clinical trials of bosentan, sildenafil and tadalafil with large sample size and long-term follow-up are needed to validate their efficacy, safety and pharmacokinetics to provide tailor-made drug therapies for this life-threatening condition.

Declaration of interest

W.Zhao has received funding from National Science and Technology Major Projects for ‘Major New Drugs Innovation and Development’ (2017ZX09304029-002), Young Taishan Scholars Program of Shandong Province and Qilu Young Scholars Program of Shandong University. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was funded by National Science and Technology Major Projects for ‘Major New Drugs Innovation and Development’ [2017ZX09304029-002], Young Taishan Scholars Program of Shandong Province and Qilu Young Scholars Program of Shandong University.