Sildenafil exposure in neonates with pulmonary hypertension after administration via a nasogastric tube.
Arch Dis Child Fetal Neonatal Ed
; 95(2): F109-14, 2010 Mar.
Article
em En
| MEDLINE
| ID: mdl-19949232
ABSTRACT
OBJECTIVE:
To describe the pharmacokinetics and exposure of oral sildenafil (SIL) in neonates (2-5 kg) with pulmonary hypertension (PH).DESIGN:
We included 11 neonates (body weight 2-5 kg, postnatal age 2-121 days) who received SIL and extracorporeal membrane oxygenation (ECMO) treatment for PH. SIL capsules were given via a nasogastric tube. Blood samples were collected via a pre-existing arterial line to quantify SIL and metabolite plasma levels (219 samples). Non-linear mixed effects modelling was used to describe SIL and desmethylsildenafil (DMS) pharmacokinetics.RESULTS:
A one-compartment model was suitable for SIL and DMS. Interpatient and intrapatient variability for clearance at 100% bioavailability were 87% and 27% (SIL) and 62% and 26% (DMS). Patient weight, postnatal age and post-ECMO time did not explain variability. Concomitant fluconazole use was associated with a 47% reduction in SIL clearance. The exposure expressed as average plasma concentration area under the curve over 24 h (AUC(24 (SIL+DMS))) ranged from 625 to 13 579 ng/h/ml. An oral dose of 4.2 mg/kg/24 h would lead to a median AUC(24 (SIL+DMS)) of 2650 ng/h/ml equivalent to 20 mg three times a day in adults. Interpatient variability was large, with a simulated AUC(24 (SIL+DMS)) range (10th and 90th percentiles) of 1000-8000 ng/h/ml.CONCLUSIONS:
SIL pharmacokinetics are highly variable in post-ECMO neonates and infants. In a median patient, the current dose regimen of 0.5-2.0 mg/kg four times a day leads to an exposure comparable to the recommended adult dose of 20 mg four times a day. Careful dose titration, based on efficacy and the occurrence of hypotension, remains necessary. Follow-up research should include appropriate pharmacodynamic endpoints, with a population pharmacokinetic/pharmacodynamic analysis to assign a suitable exposure window or target concentration.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Fosfodiesterase
/
Piperazinas
/
Sulfonas
/
Oxigenação por Membrana Extracorpórea
/
Hipertensão Pulmonar
/
Anti-Hipertensivos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
/
Infant
/
Newborn
Idioma:
En
Revista:
Arch Dis Child Fetal Neonatal Ed
Assunto da revista:
PEDIATRIA
/
PERINATOLOGIA
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Holanda