مؤتمر
Presentation1_PBPK-based dose finding for sildenafil in pregnant women for antenatal treatment of congenital diaphragmatic hernia.pdf
| العنوان: | Presentation1_PBPK-based dose finding for sildenafil in pregnant women for antenatal treatment of congenital diaphragmatic hernia.pdf |
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| المؤلفون: | Julia Macente, Nina Nauwelaerts, Francesca M. Russo, Jan Deprest, Karel Allegaert, Bart Lammens, Rodolfo Hernandes Bonan, Jessica M. Turner, Sailesh Kumar, Andrea Diniz, Frederico S. Martins, Pieter Annaert |
| سنة النشر: | 2023 |
| المجموعة: | Frontiers: Figshare |
| مصطلحات موضوعية: | Pharmacology, Basic Pharmacology, Clinical Pharmacology and Therapeutics, Clinical Pharmacy and Pharmacy Practice, Pharmaceutical Sciences, Pharmacogenomics, Toxicology (incl. Clinical Toxicology), Pharmacology and Pharmaceutical Sciences not elsewhere classified, physiologically-based pharmacokinetic modelling, PBPK, model informed drug development, MIDD, sildenafil, revatio, congenital diaphragmatic hernia, pregnant women |
| الوصف: | Sildenafil is a potent vasodilator and phosphodiesterase type five inhibitor, commercially known as Revatio ® and approved for the treatment of pulmonary arterial hypertension. Maternal administration of sildenafil during pregnancy is being evaluated for antenatal treatment of several conditions, including the prevention of pulmonary hypertension in fetuses with congenital diaphragmatic hernia. However, determination of a safe and effective maternal dose to achieve adequate fetal exposure to sildenafil remains challenging, as pregnancy almost always is an exclusion criterion in clinical studies. Physiologically-based pharmacokinetic (PBPK) modelling offers an attractive approach for dose finding in this specific population. The aim of this study is to exploit physiologically-based pharmacokinetic modelling to predict the required maternal dose to achieve therapeutic fetal exposure for the treatment congenital diaphragmatic hernia. A full-PBPK model was developed for sildenafil and N-desmethyl-sildenafil using the Simcyp simulator V21 platform, and verified in adult reference individuals, as well as in pregnant women, taking into account maternal and fetal physiology, along with factors known to determine hepatic disposition of sildenafil. Clinical pharmacokinetic data in mother and fetus were previously obtained in the RIDSTRESS study and were used for model verification purposes. Subsequent simulations were performed relying either on measured values for fetal fraction unbound (fu = 0.108) or on values predicted by the simulator (fu = 0.044). Adequate doses were predicted according to the efficacy target of 15 ng/mL (or 38 ng/mL) and safety target of 166 ng/mL (or 409 ng/mL), assuming measured (or predicted) fu values, respectively. Considering simulated median profiles for average steady state sildenafil concentrations, dosing regimens of 130 mg/day or 150 mg/day (administered as t.i.d.), were within the therapeutic window, assuming either measured or predicted fu values, respectively. For safety reasons, ... |
| نوع الوثيقة: | conference object |
| اللغة: | unknown |
| العلاقة: | https://figshare.com/articles/presentation/Presentation1_PBPK-based_dose_finding_for_sildenafil_in_pregnant_women_for_antenatal_treatment_of_congenital_diaphragmatic_hernia_pdf/22267321Test |
| DOI: | 10.3389/fphar.2023.1068153.s001 |
| الإتاحة: | https://doi.org/10.3389/fphar.2023.1068153.s001Test https://figshare.com/articles/presentation/Presentation1_PBPK-based_dose_finding_for_sildenafil_in_pregnant_women_for_antenatal_treatment_of_congenital_diaphragmatic_hernia_pdf/22267321Test |
| حقوق: | CC BY 4.0 |
| رقم الانضمام: | edsbas.F7828B01 |
| قاعدة البيانات: | BASE |
| DOI: | 10.3389/fphar.2023.1068153.s001 |
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