Eur J Clin Pharmacol. 2019 Nov 18. doi: 10.1007/s00228-019-02767-1. [Epub ahead of print]
https://www.ncbi.nlm.nih.gov/pubmed/31740991
Pharmacokinetic modeling of intravenous sildenafil in newborns with congenital diaphragmatic hernia.
Cochius-den Otter SCM1, Kipfmueller F2, de Winter BCM3, Allegaert K4,5, Tibboel D4, Mueller A2, Koch BCP3.
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Abstract
PURPOSE:
We 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.
METHODS:
Twenty-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.
RESULTS:
A 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.
CONCLUSIONS:
This 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.
KEYWORDS:
Cardiovascular tolerance; Congenital diaphragmatic hernia; Modeling; Pharmacokinetics; SildenafilPMID: 31740991 DOI: 10.1007/s00228-019-02767-1
