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PBPK-based dose finding for sildenafil in pregnant women for antenatal treatment of congenital diaphragmatic hernia.
Macente, Julia; Nauwelaerts, Nina; Russo, Francesca M; Deprest, Jan; Allegaert, Karel; Lammens, Bart; Hernandes Bonan, Rodolfo; Turner, Jessica M; Kumar, Sailesh; Diniz, Andrea; Martins, Frederico S; Annaert, Pieter.
Afiliación
  • Macente J; Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
  • Nauwelaerts N; Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
  • Russo FM; Gynecology and Obstetrics, UZ Leuven, Leuven, Belgium.
  • Deprest J; Gynecology and Obstetrics, UZ Leuven, Leuven, Belgium.
  • Allegaert K; Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
  • Lammens B; Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
  • Hernandes Bonan R; Department of Clinical Pharmacy, Erasmus MC, Rotterdam, Netherlands.
  • Turner JM; BioNotus GCV, Niel, Belgium.
  • Kumar S; BioNotus GCV, Niel, Belgium.
  • Diniz A; Mater Research Institute, University of Queensland, Brisbane, QLD, Australia.
  • Martins FS; Mater Research Institute, University of Queensland, Brisbane, QLD, Australia.
  • Annaert P; Pharmacokinetics and Biopharmaceutical Laboratory (PKBio), Department of Pharmacy, State University of Maringa, Maringa, Brazil.
Front Pharmacol ; 14: 1068153, 2023.
Article en En | MEDLINE | ID: mdl-36998614
ABSTRACT
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, dosing should be initiated at 130 mg/day, under therapeutic drug monitoring. Additional experimental measurements should be performed to confirm accurate fetal (and maternal) values for fu. Additional characterization of pharmacodynamics in this specific population is required and may lead to further optimization of the dosing regimen.
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Texto completo: 1 Base de datos: MEDLINE Tipo de estudio: Diagnostic_studies / Prognostic_studies Idioma: En Revista: Front Pharmacol Año: 2023 Tipo del documento: Article País de afiliación: Bélgica

Texto completo: 1 Base de datos: MEDLINE Tipo de estudio: Diagnostic_studies / Prognostic_studies Idioma: En Revista: Front Pharmacol Año: 2023 Tipo del documento: Article País de afiliación: Bélgica