Population pharmacokinetics of sildenafil in extremely premature infants.
Administration, Oral
Cohort Studies
Cytochrome P-450 CYP3A
/ blood
Fluconazole
/ administration & dosage
Gestational Age
Humans
Hypertension, Pulmonary
/ blood
Infant
Infant, Newborn
Infant, Premature
/ blood
Infant, Premature, Diseases
/ blood
Injections, Intravenous
Models, Biological
Phosphodiesterase 5 Inhibitors
/ administration & dosage
Sildenafil Citrate
/ administration & dosage
pharmacokinetics
premature infants
sildenafil
Journal
British journal of clinical pharmacology
ISSN: 1365-2125
Titre abrégé: Br J Clin Pharmacol
Pays: England
ID NLM: 7503323
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
26
03
2019
revised:
06
08
2019
accepted:
22
08
2019
pubmed:
3
9
2019
medline:
29
9
2020
entrez:
3
9
2019
Statut:
ppublish
Résumé
To characterize the population pharmacokinetics (PK) of sildenafil and its active metabolite, N-desmethyl sildenafil (DMS), in premature infants. We performed a multicentre, open-label trial to characterize the PK of sildenafil in infants ≤28 weeks gestation and < 365 postnatal days (cohort 1) or < 32 weeks gestation and 3-42 postnatal days (cohort 2). In cohort 1, we obtained PK samples from infants receiving sildenafil as ordered per the local standard of care (intravenous [IV] or enteral). In cohort 2, we administered a single IV dose of sildenafil and performed PK sampling. We performed a population PK analysis and dose-exposure simulations using the software NONMEM®. We enrolled 34 infants (cohort 1 n = 25; cohort 2 n = 9) and collected 109 plasma PK samples. Sildenafil was given enterally (0.42-2.09 mg/kg) in 24 infants in cohort 1 and via IV (0.125 or 0.25 mg/kg) in all infants in cohort 2. A 2-compartment PK model for sildenafil and 1-compartment model for DMS, with presystemic conversion of sildenafil to DMS, characterized the data well. Coadministration of fluconazole (n = 4), a CYP3A inhibitor, resulted in an estimated 59% decrease in sildenafil clearance. IV doses of 0.125, 0.5 and 1 mg/kg every 8 hours (in the absence of fluconazole) resulted in steady-state maximum sildenafil concentrations that were generally within the range of those reported to inhibit phosphodiesterase type 5 activity in vitro. We successfully characterized the PK of sildenafil and DMS in premature infants and applied the model to inform dosing for a follow-up, phase II study.
Identifiants
pubmed: 31475367
doi: 10.1111/bcp.14111
pmc: PMC6955411
doi:
Substances chimiques
Phosphodiesterase 5 Inhibitors
0
Fluconazole
8VZV102JFY
Sildenafil Citrate
BW9B0ZE037
Cytochrome P-450 CYP3A
EC 1.14.14.1
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2824-2837Subventions
Organisme : NICHD NIH HHS
ID : K23 HD083465
Pays : United States
Organisme : NIAID NIH HHS
ID : K24 AI143971
Pays : United States
Organisme : NICHD NIH HHS
ID : HHSN275201000003I
Pays : United States
Organisme : NHLBI NIH HHS
ID : K24 HL143283
Pays : United States
Organisme : NIAAA NIH HHS
ID : HHSN275201000003C
Pays : United States
Informations de copyright
© 2019 The British Pharmacological Society.
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