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Modélisation de l’effet du favipiravir sur la dynamique viro-immunologique de la maladie à virus Ebola et implications pour son évaluation clinique / Modeling the effect of favipiravir on the viro-immunological dynamics of Ebola virus disease and implications in clinical evaluationMadelain, Vincent 19 November 2018 (has links)
En dépit d’épidémies répétées, il n’existe pas à ce jour de thérapeutique ayant démontré son efficacité dans la maladie à virus Ebola. Sur la base d’expérimentations réalisées chez la souris et le macaque dans le cadre du consortium Reaction!, l’objectif de cette thèse visait à caractériser l’effet d’une molécule antivirale, le favipiravir, via l’implémentation de modèles mathématiques mécanistiques de l’infection et de la réponse immunitaire associée. L’approche utilisée pour construire ces modèles et en estimer les paramètres reposait sur les modèles non linéaires à effets mixtes. Un premier travail a permis d’explorer la relation concentration-effet sur la charge virale plasmatique chez la souris. Le second projet a conduit à caractériser la pharmacocinétique non linéaire dose et temps dépendante du favipiravir chez le macaque, en vue d’identifier les schémas posologiques pertinents pour la réalisation des études d’efficacité chez l’animal infecté. Au décours de leur réalisation, l’intégration des données virologiques et immunitaires générées au sein d’un modèle conjoint a permis de caractériser un effet modéré du favipiravir sur la réplication virale, mais suffisant pour limiter le développement d’une réaction inflammatoire délétère, et ainsi améliorer le taux de survie des animaux traités. Les simulations réalisées avec ce modèle ont pu souligner l’impact déterminant du délai d’initiation du traitement sur la survie. Ces résultats incitent à la poursuite de l’évaluation clinique du favipiravir, en favorisant des essais de prophylaxie ou post exposition. Enfin, un dernier travail a démontré l’absence de potentialisation du favipiravir par la ribavirine dans Ebola. / In spite of recurrent outbreaks, no therapeutics with demonstrated clinical efficacy are available in Ebola virus disease. Based on experimentations performed by Reaction! Consortium in mice and macaques, this thesis aimed to characterize the effect of an antiviral drug, favipiravir, using mechanistic mathematical models of the infection and associated immune response. The approach to build models and estimate parameters relied on nonlinear mixed effect models. The first project of this thesis explored the concentration-effect relationship on the viremia in mice. Then, a second project allowed to characterize the pharmacokinetics of favipiravir in macaques, underlying dose and time non linearity, and to identify relevant dosing regimen for efficacy experiments in infected animals. Once these experiments completed, the integration of the virological and immunological data into a mechanistic joint model shed light on the effect of favipiravir. The moderate inhibition of the viral replication resulting from the favipiravir plasma concentrations was enough to limit the development of a deleterious inflammatory response, and thus improve the survival rate of treated macaques. Simulations performed with this model underlined the crucial impact of the treatment initiation delay on survival. These results encourage the pursuit of the clinical evaluation of favipiravir in prophylaxis or post exposure trials. Finally, a last project demonstrated the lack of benefit of ribavirin addition to favipiravir in Ebola virus disease.
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Modeling The Population Dynamics Of Erythrocytes To Identify Optimal Drug Dosages For The Treatment Of Hepatitis C Virus InfectionKrishnan, Sheeja M 07 1900 (has links) (PDF)
The current treatment for hepatitis C virus (HCV) infection – combination therapy
with pegylated interferon and ribavirin – elicits sustained responses in only ~50% of
the patients treated. Greater cumulative exposure to ribavirin increases response to
interferon-ribavirin combination therapy. A key limitation, however, is the toxic sideeffect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus
requires striking a balance between the antiviral and hemolytic activities of ribavirin.
Current models of viral kinetics describe the enhancement of treatment response due
to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and
precludes rational optimization of combination therapy.
Here, we develop a new mathematical model of the population dynamics of erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients.
Based on the assumption that ribavirin accumulation decreases erythrocyte lifespan in a dose-dependent manner, model predictions capture several independent
experimental observations of the accumulation of ribavirin in erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy,
estimate the reduced erythrocyte lifespan in patients and describe inter-patient
variations in the severity of ribavirin-induced anemia. Further, model predictions
estimate the threshold ribavirin exposure beyond which anemia becomes intolerable
and suggest guidelines for the usage of growth hormones. A small fraction of the
population (~30%) with polymorphisms in the ITPA gene shows protection from
ribavirin-induced anemia. The optimum dosage of ribavirin that can be tolerated is
then dependent on the ITPA polymorphisms. Coupled with a previous population
pharmacokinetic study, our model yields a facile formula for estimating the optimum
dosage given a patient’s weight, creatinine clearance, pretreatment hemoglobin levels,
and ITPA polymorphism. The reduced lifespan we predict is in agreement with independent measurements from breath tests as well as estimates derived from in vitro studies of ATP depletion. The latter estimates also agree with the extent of ATP depletion due to ribavirin that we predict from a detailed analysis of the nucleoside metabolism in erythrocytes.
Our model thus facilitates in conjunction with models of viral kinetics the rational
identification of treatment protocols. Our formula for optimum dose presents an
avenue for personalizing ribavirin dosage. By keeping anemia tolerable, the predicted
optimal dosage may improve adherence, reduce the need for drug monitoring, and
increase response rates.
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