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.

Additional Metadata
Keywords Cardiovascular tolerance, Congenital diaphragmatic hernia, Modeling, Pharmacokinetics, Sildenafil
Persistent URL dx.doi.org/10.1007/s00228-019-02767-1, hdl.handle.net/1765/121900
Journal European Journal of Clinical Pharmacology
Citation
Cochius-Den Otter, S.C.M, Kipfmueller, F. (Florian), de Winter, B.C.M, Allegaert, K.M, Tibboel, D, Mueller, A. (Andreas), & Koch, B.C.P. (2019). Pharmacokinetic modeling of intravenous sildenafil in newborns with congenital diaphragmatic hernia. European Journal of Clinical Pharmacology. doi:10.1007/s00228-019-02767-1