Population Pharmacokinetics and Dosage Individualization of Oral Pulmonary Vasodilators in PPHN

Study Overview
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Brief Summary
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The use of bosentan, sildenafil and tadalafil in neonates with persistent pulmonary hypertension (PPHN) depends mostly on the empirical experience of pediatricians. Moreover, the recommended dose of those three drugs in treating PPHN remains controversial. Therefore, our aim is to study the pharmacokinetics and pharmacodynamics of bosentan, sildenafil and tadalafil in neonates of PPHN then dose a tailor-made therapeutic regimen.

Official Title
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Population Pharmacokinetics and Dosage Individualization of Bosentan, Sildenafil and Tadalafil in Persistent Pulmonary Hypertension of the Newborn

Conditions
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Persistent Pulmonary Hypertension of the Newborn

Intervention / Treatment
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* Drug: Bosentan Tablets
* Drug: Sildenafil Tablet
* Drug: Tadalafil Tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: postnatal age ≤ 28 days; Patients have been diagnosed with PPHN; Bosentan, sildenafil and/or tadalafil used as part of regular treatment. Parental written consent Exclusion Criteria: Expected survival time less than the treatment cycle; Major congenital malformations; Undergoing surgery within the first week of life; Receiving other systemic trial drug therapy; Other factors that the researcher considers unsuitable for inclusion.

Ages Eligible for Study
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Maximum Age: 28 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Treatment(bosentan, sildenafil and tadalafil)<br> | Drug: Bosentan Tablets<br>* 2mg/kg, bid<br>Drug: Sildenafil Tablet<br>* 1mg/kg, q6h/q8h<br>Drug: Tadalafil Tablets<br>* 1mg/kg, qd<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygenation index | Oxygenation index=(fraction of inspired oxygen*mean airway pressure)/the partial pressure of arterial oxygen | The first 72 hours of the initial treatment | 
| The change of hemodynamics | Pulmonary artery pressure (mmHg) Alveolar-arterial gradient (mmHg) | Through study completion, an average of 5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of hospitalization | Duration of initial therapy | Within the first 28 days of patients' life | 
| Death | Death in the first 28 days of life | Within the first 28 days of patients' life | 
| Adverse events | Drug-related adverse events and serious adverse events | Through study completion, an average of 5 days | 
| Sequelae of PPHN | Including cerebral palsy, hearing impairment, neurodevelopmental outcome etc | Through study completion and a 6-month visit | 
| The need of extra support | Besides the initial therapy (bosentan, sildenafil and/or tadalafil), other support such as inhaled nitric oxide (iNO), inotropic agents or Extracorporeal Membrane Oxygenation (ECMO) | Through study completion, an average of 5 days | 
| Pulse oxygen saturation | Pulse oxygen saturation（%） | The first 72 hours of the initial treatment |