Placental transfer of Letermovir & Maribavir in the ex vivo human cotyledon perfusion model. New perspectives for in utero treatment of congenital cytomegalovirus infection

Valentine Faure Bardon, Gilles Peytavin, Minh Patrick Lê, Tiffany Guilleminot, Elisabeth Elefant, Julien Stirnemann, Marianne Leruez-Ville, Yves Ville, Valentine Faure Bardon, Gilles Peytavin, Minh Patrick Lê, Tiffany Guilleminot, Elisabeth Elefant, Julien Stirnemann, Marianne Leruez-Ville, Yves Ville

Abstract

Background: Congenital cytomegalovirus infection can lead to severe sequelae. When fetal infection is confirmed, we hypothesize that fetal treatment could improve the outcome. Maternal oral administration of an effective drug crossing the placenta could allow fetal treatment. Letermovir (LMV) and Maribavir (MBV) are new CMV antivirals, and potential candidates for fetal treatment.

Methods: The objective was to investigate the placental transfer of LMV and MBV in the ex vivo method of the human perfused cotyledon. Term placentas were perfused, in an open-circuit model, with LMV or MBV at concentrations in the range of clinical peak plasma concentrations. Concentrations were measured using ultraperformance liquid chromatography coupled with tandem mass spectrometry. Mean fetal transfer rate (FTR) (fetal (FC) /maternal concentration), clearance index (CLI), accumulation index (AI) (retention of each drug in the cotyledon tissue) were measured. Mean FC were compared with half maximal effective concentrations of the drugs (EC50(LMV) and EC50(MBV)).

Results: For LMV, the mean FC was (± standard deviation) 1.1 ± 0.2 mg/L, 1,000-fold above the EC50(LMV). Mean FTR, CLI and AI were 9 ± 1%, 35 ± 6% and 4 ± 2% respectively. For MBV, the mean FC was 1.4 ± 0.2 mg/L, 28-fold above the EC50(MBV). Mean FTR, CLI and AI were 10 ± 1%, 50 ± 7% and 2 ± 1% respectively.

Conclusions: Drugs' concentrations in the fetal side should be in the range for in utero treatment of fetuses infected with CMV as the mean FC was superior to the EC50 for both molecules.

Conflict of interest statement

- Valentine Faure Bardon: No conflict - Gilles Peytavin has received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies, including Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare. - Minh Patrick Lê has received travel grants from Bristol-Myers Squibb and Janssen. - Tiffany Guilleminot: No conflict - Elisabeth Elefant: No conflict - Julien Stirnemann: No conflict - Marianne Leruez-Ville declares receiving financial support for meeting expenses from BioMerieux outside the submitted work. - Yves Ville: reports non-financial support from Ferring SAS, non-financial support from Siemens Health Care, non-financial support from GE medical, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1
Mean Letermovir concentrations (Panel A) and mean Maribavir concentrations (Panel B) for all placentas. Panel A: Mean (± SD) maternal (full triangle) and fetal (empty triangle) concentrations of Letermovir (mg/L). Panel B: Mean (± SD) maternal (full square) and fetal (empty square) concentrations of Maribavir (mg/L).

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