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Tytuł pozycji:

Pharmacokinetics and pharmacodynamics of sildenafil in fetal lambs on extracorporeal support.

Tytuł:
Pharmacokinetics and pharmacodynamics of sildenafil in fetal lambs on extracorporeal support.
Autorzy:
De Bie FR; Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States; MyFetUZ, Department of Development and Regeneration, KU Leuven, Leuven, Belgium. Electronic address: .
Russo FM; Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States.
Van Brantegem P; Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
Coons BE; Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States.
Moon JK; Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States.
Yang Z; Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States.
Pang C; Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States.
Senra JC; Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States.
Omann C; Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States.
Annaert P; Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
Allegaert K; MyFetUZ, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium; Department of Hospital Pharmacy, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Davey MG; Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States.
Flake AW; Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, United States.
Deprest J; MyFetUZ, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
Źródło:
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2021 Nov; Vol. 143, pp. 112161. Date of Electronic Publication: 2021 Sep 16.
Typ publikacji:
Journal Article
Język:
English
Imprint Name(s):
Publication: Paris : Editions Scientifiques Elsevier
Original Publication: New York, N.Y. : Masson Pub. USA, Inc., c1982-
MeSH Terms:
Extracorporeal Circulation*
Fetal Therapies*
Aorta/*drug effects
Pulmonary Artery/*drug effects
Sildenafil Citrate/*pharmacokinetics
Vasodilation/*drug effects
Vasodilator Agents/*pharmacokinetics
Animals ; Aorta/diagnostic imaging ; Aorta/physiopathology ; Arterial Pressure/drug effects ; Gestational Age ; Infusions, Intravenous ; Models, Biological ; Pulmonary Artery/diagnostic imaging ; Pulmonary Artery/physiopathology ; Sheep, Domestic ; Sildenafil Citrate/administration & dosage ; Sildenafil Citrate/blood ; Vascular Resistance/drug effects ; Vasodilator Agents/administration & dosage ; Vasodilator Agents/blood
Contributed Indexing:
Keywords: Extracorporeal circulation; Fetal lamb; Fetal therapies; Sildenafil citrate
Substance Nomenclature:
0 (Vasodilator Agents)
BW9B0ZE037 (Sildenafil Citrate)
Entry Date(s):
Date Created: 20210919 Date Completed: 20220127 Latest Revision: 20220427
Update Code:
20240105
DOI:
10.1016/j.biopha.2021.112161
PMID:
34537676
Czasopismo naukowe
Background: Maternal transplacental administration of sildenafil is being considered for a variety of fetal conditions. Clinical translation also requires evaluation of fetal safety in a higher species, such as the fetal lamb. Experiments with the pregnant ewe are curtailed by minimal transplacental transfer as well as limited access to the fetus. The EXTra-uterine Environment for Neonatal Development (EXTEND) model renders the isolated fetal lamb readily accessible and allows for direct fetal administration of sildenafil.
Methods: Five fetal lambs were placed on extracorporeal support in the EXTEND device and received continuous intravenous (IV) sildenafil (0.3-0.5-0.7 mg/kg/24hr) for a duration of one to seven days. Plasma sildenafil concentrations were sampled at regular intervals to establish the pharmacokinetic profile using population pharmacokinetic modeling. Serial Doppler ultrasound examination, continuous non-invasive hemodynamic monitoring and blood gas analysis were done to evaluate the pharmacodynamic effects and fetal response.
Findings: The target concentration range (47-500 ng/mL) was attained with all doses. Sildenafil induced an immediate and temporary reduction of pulmonary vascular resistance, mean arterial pressure and circuit flow, without change in fetal lactate levels and acid-base status. The duration of the systemic effects increased with the dose.
Interpretation: Immediate temporary pulmonary vascular and systemic hemodynamic changes induced by sildenafil were biochemically well tolerated by fetal lambs on extracorporeal support, with the 0.5 mg/kg/24 h dose balancing rapid attainment of target concentrations with short-lived systemic effects.
Research in Context: None.
Search Strategy Before Undertaking the Study: A literature review was conducted searching online databases (Medline, Embase and Cochrane), using search terms: fetal OR prenatal OR antenatal AND sildenafil, without time-limit and excluding human studies. Where relevant, investigators were contacted in order to avoid duplication of work.
Evidence Before This Study: Prenatal therapy with sildenafil, a phosphodiesterase-5 inhibitor with vasodilatory and anti-remodeling effects on vascular smooth muscle cells, has been considered for a variety of fetal conditions. One multicenter clinical trial investigating the benefit of sildenafil in severe intrauterine growth restriction (the STRIDER-trial) was halted early due to excess mortality in the sildenafil-exposed arm at one treatment site. Such findings demonstrate the importance of extensive preclinical safety assessment in relevant animal models. Transplacentally administered sildenafil leads to decreased pulmonary arterial muscularization, preventing or reducing the occurrence of pulmonary hypertension in rat and rabbit fetuses with diaphragmatic hernia (DH). Validation of these results in a higher and relevant animal model, e.g. fetal lambs, is the next step to advance clinical translation. We recently demonstrated that, in contrast to humans, transplacental transfer of sildenafil in sheep is minimal, precluding the in vivo study of fetal effects at target concentrations using the conventional pregnant ewe model.
Added Value of This Study: We therefore used the extracorporeal support model for fetal lambs, referred to as the EXTra-uterine Environment for Neonatal Development (EXTEND) system, bypassing placental and maternal metabolism, to investigate at what dose the target concentrations are reached, and what the fetal hemodynamic impact and response are. Fetal hemodynamic and metabolic tolerance to sildenafil are a crucial missing element on the road to clinical translation. This is therefore the first study investigating the pharmacokinetics, hemodynamic and biochemical effects of clinical-range concentrations of sildenafil in fetal lambs, free from placental and maternal interference.
Implications of All the Available Evidence: We demonstrated self-limiting pulmonary vasodilation, a decrease of both systemic arterial pressures and circuit flows, induced by clinical range concentrations of sildenafil, without the development of fetal acidosis. This paves the way for further investigation of prenatal sildenafil in fetal lambs on extracorporeal support. A dose of 0.5 mg/kg/24 h offered the best trade-off between rapid achievement of target concentrations and shortest duration of systemic effects. This is also the first study using the EXTEND as a model for pharmacotherapy during pregnancy.
(Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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