Les enfants diffèrent des adultes non seulement en termes de dimension corporelle mais aussi en termes physiologiques. En effet, les phénomènes de développement et maturation interviennent au cours de la croissance. Ces processus ne sont pas linéaires et induisent des différences pharmacocinétiques et pharmacodynamiques. Ainsi, contrairement à la pratique commune, il n’est pas approprié de déterminer les posologies pédiatriques directement à partir des doses adultes. Étudier la pharmacocinétique chez l’enfant est fondamental pour pouvoir déterminer les posologies à administrer. La méthodologie idéale est l’analyse de population à travers des modèles non-linéaires à effets mixtes. Cependant, même si cette méthode permet l’analyse de données éparses et déséquilibrées, le manque de données individuelles doit être compensé par l’inclusion de plus d’individus. Cela pose un problème lorsque l’indication du traitement est une maladie rare, comme le sont les syndromes épileptiques de l’enfance. Dans ce cas, l’extrapolation de modèles adultes à la population pédiatrique peut s’avérer avantageuse. L’objectif de ce travail de thèse était d’évaluer les recommandations posologiques d’antiépileptiques lorsque des données pharmacocinétiques pédiatriques sont suffisamment informatives pour permettre la construction d’un modèle, ou lorsque celles-ci ne sont pas suffisamment importantes ou ne peuvent pas être exploitées correctement. Dans un premier temps, un modèle parent-métabolite de l’oxcarbazépine et de son dérivé mono-hydroxylé (MHD) a été développé chez l’enfant épileptique âgé de 2 à 12 ans. Ce modèle a permis de mettre en évidence que les plus jeunes enfants nécessitent des doses plus élevées, ainsi que les patients co-traités avec des inducteurs enzymatiques. Un modèle a aussi été développé pour les enfants épileptiques de 1 à 18 ans traités avec la formulation de microsphères à libération prolongée d’acide valproïque. Ce modèle a tenu en compte le flip-flop associé à la formulation et la relation non-linéaire entre la clairance et la dose due à la liaison protéique saturable de façon mécanistique. Encore une fois, il a été mis en évidence le besoin de doses plus élevées pour les enfants plus jeunes. Puis, un modèle adulte du vigabatrin a été extrapolé à l’enfant pour déterminer les posologies permettant d’atteindre des expositions similaires à l’adulte pour traiter les épilepsies focales résistantes. A partir des résultats obtenus, qui sont en accord avec les conclusions d’essais cliniques, nous avons pu proposer une dose de maintenance idéale dans cette indication. Enfin, nous avons étudié la pertinence de l’extrapolation par allométrie théorique dans un contexte de non-linéarité avec l’exemple du stiripentol. Nous avons pu en conclure que cette méthode semble apporter de bonnes prédictions à partir de l’âge de 8 ans, contrairement aux molécules à élimination linéaire où cela semble correct à partir de 5 ans. En conclusion, nous avons pu tester et comparer différentes approches pour aider à la détermination de recommandations posologiques chez l’enfant. L’étude de la pharmacocinétique pédiatrique par des essais spécifiques reste indispensable au bon usage du médicament. / Children greatly differ from adults not only in terms of size but also in physiological terms. Indeed, developmental changes occur during growth due to maturation. These processes occur in a nonlinear fashion and can cause pharmacokinetic and pharmacodynamic differences. Thus, oppositely to common practice, it is not appropriate to scale pediatric doses directly and linearly from adults. The study of pharmacokinetics in children is then essential to determine those pediatric dosages. The more commonly used methodology is population analysis through non-linear mixed effects models. This method allows the analysis of sparse and unbalanced data. In return, the lack of individual data has to be balanced with the inclusion of more individuals. This can be a problem when the indication of treatment is a rare disease, as are epileptic syndromes of childhood. In this case, extrapolation of adult pharmacokinetic models to the pediatric population may be interesting. The objective of this thesis was to evaluate the dosage recommendations of antiepileptic drugs when pediatric pharmacokinetic data are sufficient to be modeled, and when they are not, extrapolating adequately adult information. Firstly, a parent-metabolite model of oxcarbazepine and its monohydroxy derivative (MHD) was developed in epileptic children aged 2 to 12 years. This model showed that younger children require higher doses, as well as patients co-treated with enzyme inducers. A model was also developed for epileptic children aged 1 to 18 years treated with a valproic acid sustained release microsphere formulation. This model took into account the flip-flop associated with the formulation and the non-linear relationship between clearance and dose caused by a saturable protein binding. Again, the need for higher doses for younger children was highlighted. Then, an adult model of vigabatrin was extrapolated to children to determine which doses allow to achieve exposures similar to adults in resistant focal onset seizures. From the results obtained, which are in agreement with the conclusions of clinical trials, we have been able to propose an ideal maintenance dose for this indication. Finally, we studied the relevance of extrapolation by theoretical allometry in a context of non-linearity with the example of stiripentol. We concluded that this method seems to provide good predictions from the age of 8, unlike the linear elimination molecules where it seems correct from 5 years. In conclusion, we were able to test and compare different approaches to help determine dosing recommendations in children. The study of pediatric pharmacokinetics in specific trials remains essential for the proper use of drugs.

A dificuldade de realização de estudos clínicos com a população pediátrica favorece a prescrição off-label de medicamentos. Paralelamente, existe uma grande diversidade de fontes de informações sobre medicamentos disponíveis para consulta e diferentes formas de expressar doses para a pediatria, podendo resultar em padrões variados no uso de medicamentos. Este estudo avaliou a concordância de fontes de informação, em nível nacional e internacional, que orientam a prescrição pediátrica de antimicrobianos para faringotonsilite, otite média aguda (OMA) e rinossinusite, em relação ao fármaco de escolha, à posologia e aos tipos de referências utilizadas para sua elaboração. Foram selecionados documentos de entidades brasileiras e estrangeiras e as bulas dos medicamentos neles mencionados, totalizando 23 documentos diferentes para as três doenças avaliadas. A classe das penicilinas foi prevalente como terapia de primeira escolha nas três doenças estudadas, contudo houve grande variação nas doses indicadas e no modo como elas são expressas. A idade mínima para uso foi informada em 51,2% das fontes, sendo menos recorrente nas fontes nacionais. A duração do tratamento esteve presente em 66,7% dos fármacos indicados nas fontes. De forma geral, as fontes analisadas para as três doenças avaliadas citam principalmente referências classificadas como artigos de revisão e estudos experimentais, seguidos dos formulários e listas oficiais e consensos, diretrizes e manuais para embasar seus dados. Os resultados encontrados neste estudo reforçam a necessidade de estimular a realização de ensaios clínicos e/ ou estudos de farmacometria para a definição de doses de antimicrobianos para a pediatria, assim como, a harmonização das informações disponibilizadas para orientar a prescrição. / The difficulty of conducting clinical studies with the pediatric population favors off-label prescribing. At the same time, there is easy access to a great diversity of sources of information about drugs and different ways of expressing pediatric doses. These factors have impact on drug prescription and may result in varying standards in the use of medications. The present study assessed, at national and international levels, the agreement of information sources that guide pediatric prescription of antimicrobials for pharyngotonsillitis, acute otitis media (AOM) and rhinosinusitis, in relation to the drug of choice, dosage and types of references used in its preparation. Documents from Brazilian and international entities and the package inserts of the medications mentioned in these documents were selected. To three diseases, was analyzed 23 differents documents. The penicillin class was prevalent as first-line therapy in the three diseases investigated. However, there was great variation in the doses indicated and in the way they are expressed. The minimum age for use was reported in only 51,2% of the sources, being less recurrent in the national sources. Duration of treatment was present in 66,7% of the drugs indicated in the sources. In general, the sources analyzed for the three disorders investigated most often cite references classified as review articles and experimental studies, followed by formularies and official lists and consensus, guidelines and manuals to support their data. The results obtained reinforce the need to encourage clinical trials and/or pharmacometrics studies for establishing dosing recommendations of antimicrobials for pediatric patients, as well as to harmonize the information provided to guide prescriptions.

A dificuldade de realização de estudos clínicos com a população pediátrica favorece a prescrição off-label de medicamentos. Paralelamente, existe uma grande diversidade de fontes de informações sobre medicamentos disponíveis para consulta e diferentes formas de expressar doses para a pediatria, podendo resultar em padrões variados no uso de medicamentos. Este estudo avaliou a concordância de fontes de informação, em nível nacional e internacional, que orientam a prescrição pediátrica de antimicrobianos para faringotonsilite, otite média aguda (OMA) e rinossinusite, em relação ao fármaco de escolha, à posologia e aos tipos de referências utilizadas para sua elaboração. Foram selecionados documentos de entidades brasileiras e estrangeiras e as bulas dos medicamentos neles mencionados, totalizando 23 documentos diferentes para as três doenças avaliadas. A classe das penicilinas foi prevalente como terapia de primeira escolha nas três doenças estudadas, contudo houve grande variação nas doses indicadas e no modo como elas são expressas. A idade mínima para uso foi informada em 51,2% das fontes, sendo menos recorrente nas fontes nacionais. A duração do tratamento esteve presente em 66,7% dos fármacos indicados nas fontes. De forma geral, as fontes analisadas para as três doenças avaliadas citam principalmente referências classificadas como artigos de revisão e estudos experimentais, seguidos dos formulários e listas oficiais e consensos, diretrizes e manuais para embasar seus dados. Os resultados encontrados neste estudo reforçam a necessidade de estimular a realização de ensaios clínicos e/ ou estudos de farmacometria para a definição de doses de antimicrobianos para a pediatria, assim como, a harmonização das informações disponibilizadas para orientar a prescrição. / The difficulty of conducting clinical studies with the pediatric population favors off-label prescribing. At the same time, there is easy access to a great diversity of sources of information about drugs and different ways of expressing pediatric doses. These factors have impact on drug prescription and may result in varying standards in the use of medications. The present study assessed, at national and international levels, the agreement of information sources that guide pediatric prescription of antimicrobials for pharyngotonsillitis, acute otitis media (AOM) and rhinosinusitis, in relation to the drug of choice, dosage and types of references used in its preparation. Documents from Brazilian and international entities and the package inserts of the medications mentioned in these documents were selected. To three diseases, was analyzed 23 differents documents. The penicillin class was prevalent as first-line therapy in the three diseases investigated. However, there was great variation in the doses indicated and in the way they are expressed. The minimum age for use was reported in only 51,2% of the sources, being less recurrent in the national sources. Duration of treatment was present in 66,7% of the drugs indicated in the sources. In general, the sources analyzed for the three disorders investigated most often cite references classified as review articles and experimental studies, followed by formularies and official lists and consensus, guidelines and manuals to support their data. The results obtained reinforce the need to encourage clinical trials and/or pharmacometrics studies for establishing dosing recommendations of antimicrobials for pediatric patients, as well as to harmonize the information provided to guide prescriptions.

A dificuldade de realização de estudos clínicos com a população pediátrica favorece a prescrição off-label de medicamentos. Paralelamente, existe uma grande diversidade de fontes de informações sobre medicamentos disponíveis para consulta e diferentes formas de expressar doses para a pediatria, podendo resultar em padrões variados no uso de medicamentos. Este estudo avaliou a concordância de fontes de informação, em nível nacional e internacional, que orientam a prescrição pediátrica de antimicrobianos para faringotonsilite, otite média aguda (OMA) e rinossinusite, em relação ao fármaco de escolha, à posologia e aos tipos de referências utilizadas para sua elaboração. Foram selecionados documentos de entidades brasileiras e estrangeiras e as bulas dos medicamentos neles mencionados, totalizando 23 documentos diferentes para as três doenças avaliadas. A classe das penicilinas foi prevalente como terapia de primeira escolha nas três doenças estudadas, contudo houve grande variação nas doses indicadas e no modo como elas são expressas. A idade mínima para uso foi informada em 51,2% das fontes, sendo menos recorrente nas fontes nacionais. A duração do tratamento esteve presente em 66,7% dos fármacos indicados nas fontes. De forma geral, as fontes analisadas para as três doenças avaliadas citam principalmente referências classificadas como artigos de revisão e estudos experimentais, seguidos dos formulários e listas oficiais e consensos, diretrizes e manuais para embasar seus dados. Os resultados encontrados neste estudo reforçam a necessidade de estimular a realização de ensaios clínicos e/ ou estudos de farmacometria para a definição de doses de antimicrobianos para a pediatria, assim como, a harmonização das informações disponibilizadas para orientar a prescrição. / The difficulty of conducting clinical studies with the pediatric population favors off-label prescribing. At the same time, there is easy access to a great diversity of sources of information about drugs and different ways of expressing pediatric doses. These factors have impact on drug prescription and may result in varying standards in the use of medications. The present study assessed, at national and international levels, the agreement of information sources that guide pediatric prescription of antimicrobials for pharyngotonsillitis, acute otitis media (AOM) and rhinosinusitis, in relation to the drug of choice, dosage and types of references used in its preparation. Documents from Brazilian and international entities and the package inserts of the medications mentioned in these documents were selected. To three diseases, was analyzed 23 differents documents. The penicillin class was prevalent as first-line therapy in the three diseases investigated. However, there was great variation in the doses indicated and in the way they are expressed. The minimum age for use was reported in only 51,2% of the sources, being less recurrent in the national sources. Duration of treatment was present in 66,7% of the drugs indicated in the sources. In general, the sources analyzed for the three disorders investigated most often cite references classified as review articles and experimental studies, followed by formularies and official lists and consensus, guidelines and manuals to support their data. The results obtained reinforce the need to encourage clinical trials and/or pharmacometrics studies for establishing dosing recommendations of antimicrobials for pediatric patients, as well as to harmonize the information provided to guide prescriptions.