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Pharmacocinétique / pharmacodynamie du ganciclovir chez l'enfant

Abstract : Introduction: only few pediatric studies report the pharmacokinetics and anti-CMV effect of ganciclovir (GCV), especially in patients undergoing hematopoietic stem cell transplantation (HSCT). Some exposure targets have been proposed in adults but remains unexplored in children. The main objectives of this study were to: i) model GCV concentrations in children, ii) describe blood CMV loads, using nonlinear mixed effects model, iii) quantify the therapeutic effects of antiviral drugs administered, iv) explain interindividual variability by covariates (e.g., age, weight, creatinine clearance, etc...). Material and methods: a total of 105 children on GCV or valganciclovir, followed up at Necker hospital, were included in the PK study. Among them, children undergoing HSCT were selected to investigate the antiviral effect. Blood samples were collected for routine laboratory examination. CMV loads were assessed weekly. All the data were analyzed using non-linear modeling with mixed effects. Results: a two-compartment model, with first-order absorption for valganciclovir and first-order elimination, best described the data. Bodyweight (BW) effect was represented with an allometric model. Estimated glomerular filtration rate (eGFR) and critically ill status were significantly associated with GCV elimination. Recommended doses were adequate for prophylactic treatment. However, current dosing algorithm might be associated with a high risk of under-exposure for curative therapy. Viral loads were investigated using a semi-physiologic and mechanistic model. GCV produced a 95% inhibition on CMV production constant. FSC exerted little additional antiviral effect when associated with GCV. GCV exposure impact on viral dynamics was not significant within the studied range. Lymphocyte counts had a significant effect on viral elimination. Conclusion: a high rate of pediatric exposures below adult therapeutic targets, following current GCV recommended doses, might suggest underdosing in children, especially for curative treatment. Dosing adjustment in the pediatric population should be reevaluated with respect to body weight and renal function. In this study on the concentration-effect link in HSCT children, CMV clearance was observed despite GCV AUC0-24h <40 mcg*h/mL.
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Submitted on : Friday, July 1, 2022 - 2:38:11 PM
Last modification on : Friday, August 5, 2022 - 11:57:37 AM

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Tran Bach Nguyen. Pharmacocinétique / pharmacodynamie du ganciclovir chez l'enfant. Pharmacologie. Université Paris Cité, 2021. Français. ⟨NNT : 2021UNIP5039⟩. ⟨tel-03711597⟩

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