Pharmacokinetic modeling of intravenous sildenafil in newborns with congenital diaphragmatic hernia

Suzan C M Cochius - Den Otter,Birgit C P Koch,Dick Tibboel,Karel Allegaert,Andreas Mueller,Florian Kipfmueller,Brenda C M De Winter

doi:10.1007/s00228-019-02767-1

Abstract

PurposeWe developed a pharmacokinetic model of intravenous sildenafil in newborns with congenital diaphragmatic hernia (CDH) to achieve a target plasma concentration of over 50 μg/l.MethodsTwenty-three CDH newborns with pulmonary hypertension (64 blood samples) received intravenous sildenafil. Patients received a loading dose of 0.35 mg/kg (IQR 0.16 mg/kg) for 3 h, followed by a continuous infusion of 1.5 mg/kg/day (IQR 0.1 mg/kg/day). For model development, non-linear mixed modeling was used. Inter-individual variability (IIV) and inter-occasion variability were tested. Demographic and laboratory parameters were evaluated as covariates. Normalized prediction distribution errors (NPDE) and visual predictive check (VPC) were used for model validation.ResultsA two-compartment disposition model of sildenafil and a one-compartment disposition model of desmethyl sildenafil (DMS) was observed with IIV in sildenafil and DMS clearance and volume of distribution of sildenafil. NPDE and VPC revealed adequate predictability. Only postnatal age increased sildenafil clearance. This was partly compensated by a higher DMS concentration, which also has a therapeutic effect. In this small group of patients, sildenafil was tolerated well.ConclusionsThis model for sildenafil in CDH patients shows that concentration-targeted sildenafil dosing of 0.4 mg/kg in 3 h, followed by 1.6 mg/kg/day continuous infusion achieves appropriate sildenafil plasma levels.

Highlights

MethodsCongenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm with abnormal lung development and pulmonary vasculature growth, resulting in pulmonary hypertension (PH) [1]
What is already known about this subject: - Therapy resistant pulmonary hypertension (PH) in congenital diaphragmatic hernia (CDH) patients has a high mortality rate. - Sildenafil is used for the treatment of PH, but data on optimal dosing and pharmacokinetics (PK) are lacking. - In this study, we developed a PK model for sildenafil in CDH patients
What this study adds: - An intravenous sildenafil loading dose of 0.4 mg/kg in 3 h followed by continuous infusion of 1.6 mg/kg/day achieves therapeutic sildenafil plasma levels in CDH patients in approximately 1 h. - The current PK model is the first step toward concentration range targeted sildenafil dosing in CDH patients

Summary

Introduction

Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm with abnormal lung development and pulmonary vasculature growth, resulting in pulmonary hypertension (PH) [1]. PH is one of the most important risk factors for poor outcome in infants with CDH [1, 5, 6]. High resistance in the pulmonary circulation is normal and causes most of the blood flow to bypass the lungs through the ductus arteriosus. As part of normal transition, the pulmonary vascular resistance drops immediately after birth and the blood flow through the lung vasculature increases significantly. In infants with CDH, the pulmonary vascular resistance often does not drop adequately, due to increased vascular reactivity, excessive muscularization of the pulmonary arterioles, and increased thickness of the arterial media and adventitia [8]

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