Pharmacokinetic modeling of intravenous sildenafil in newborns with congenital diaphragmatic hernia.
Eur J Clin Pharmacol
; 76(2): 219-227, 2020 Feb.
Article
in En
| MEDLINE
| ID: mdl-31740991
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Hernias, Diaphragmatic, Congenital
/
Sildenafil Citrate
/
Hypertension, Pulmonary
/
Models, Biological
Type of study:
Etiology_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
/
Newborn
Language:
En
Journal:
Eur J Clin Pharmacol
Year:
2020
Document type:
Article
Affiliation country:
Netherlands