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Optimisation des modalités thérapeutiques de l'infection à CMV en post-transplantation de moelle osseuse pédiatrique par l'étude in vitro des relations PK/PD de l'efficacité antivirale et de la toxicité cellulaire du Ganciclovir

Abstract : Human cytomegalovirus infection is still a major complication after pediatric bone marrow transplantation and can be fatal in some cases. Ganciclovir (GCV) remains the standard treatment after pediatric bone marrow transplantation even though it has a high toxicity on hematological cells. The aim of the current in vitro study was to evaluate therapeutic schedules shorter but more intensive than those actually used in vivo (14 days with target through plasma concentrations between 1 and 2 mg/mL). The impact of the intensity (1 to 20 mg/L) and duration (1 to 14 days) of GCV exposure on toxicity and effectiveness has been studied based on lymphoblastoid cell culture; infected or not with CMV. A correlation between the dose of GCV exposure and toxicity (cell counting) was found when duration of exposure exceeds 2 days. Toxicity was due to metabolism of GCV as GCV triphosphate (detection by chromatographic method coupled with mass spectrometry). Shorter durations of exposure (1 and 2 days) seemed to be as effective (viral load measurement) as longer duration of exposure for GCV concentrations between 5 and 20 mg/L. This study demonstrates for the first time that GCV exhibits a duration-dependent toxicity on hematopoietic derived cells when in vivo doses of the drug are used. They show the interest to limit the duration of treatment. Results will be integrated in a mathematical model to determine the optimal therapeutic schedule. This new regimen will be tested in a paediatric clinical trial. It should improve CMV infection treatment in immune-depressed paediatric patients.
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https://hal.univ-lorraine.fr/tel-01748413
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Audrey Janoly-Dumenil. Optimisation des modalités thérapeutiques de l'infection à CMV en post-transplantation de moelle osseuse pédiatrique par l'étude in vitro des relations PK/PD de l'efficacité antivirale et de la toxicité cellulaire du Ganciclovir. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2008. Français. ⟨NNT : 2008NAN10082⟩. ⟨tel-01748413⟩

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