There is high variability in response to cancer chemotherapies among patients. Its sources are diverse: genetic, physiologic, comorbidities, concomitant medications, environment, compliance, etc. As the therapeutic window of anticancer drugs is usually narrow, such variability may have serious consequences: severe (even life-threatening) toxicities or lack of therapeutic effect. Therefore, various approaches to individually tailor treatments and dosing regimens have been developed: a priori (based on genetic information, body size, drug elimination functions, etc.) and a posteriori (that is using information of measurements of drug exposure and/or effects). Mixed-effects modelling of pharmacokinetics and pharmacodynamics (PK-PD), combined with Bayesian maximum a posteriori probability estimation of individual effects, is the method of choice for a posteriori adjustments of dosing regimens. In this thesis, a novel approach to adjust the doses on the basis of predictions, given by a model for ordered categorical observations of toxicity, was developed and investigated by computer simulations. More technical aspects concerning the estimation of individual parameters were analysed to determine the factors of good performance of the method. These works were based on the example of capecitabine-induced hand-and-foot syndrome in the treatment of colorectal cancer. Moreover, a review of pharmacodynamic models for discrete data (categorical, count, time-to-event) was performed. Finally, PK-PD analyses of hydroxyurea in the treatment of sickle cell anemia were performed and used to compare different dosing regimens and determine the optimal measures for monitoring the treatment

Made available in DSpace on 2016-06-02T20:05:58Z (GMT). No. of bitstreams: 1 DissKBRS.pdf: 617246 bytes, checksum: 9436ee8984a49f5df072023b717747c6 (MD5) Previous issue date: 2006-02-24 / In this work we present the methodology of capture-recapture, under the classic and bayesian approach, to estimate the number of errors of software through inspection by distinct reviewers. We present the general statistical model considering independence among errors and among reviewers and consider the particular cases of equally detectable errors (homogeneous) and reviewers not equally e¢ cient (heterogeneous) and of errors not equally detectable (heterogeneous) and equally e¢ cient reviewers (homogeneous). After that, under the assumption of independence and heterogeneity among errors and independence and homogeneity among reviwers, we supposed that the heterogeneity of the errors was expressed by a classification of these in easy and di¢ cult of detecting, admitting known the probabilities of detection of an easy error and of a di¢ cult error. Finally, under the hypothesis of independence and homogeneity among errors, we presented a new model considering heterogeneity and dependence among reviewers. Besides, we presented examples with simulate and real data. / Nesta dissertação apresentamos a metodologia de captura-recaptura, sob os enfoques clássico e bayesiano, para estimar o número de erros de um software através de sua inspeção por revisores distintos. Apresentamos o modelo estatístico geral considerando independência entre erros e entre revisores e consideramos os casos particulares de erros igualmente.detectáveis (homogêneos) e revisores não igualmente eficientes (heterogêneos) e de erros não igualmente detectáveis (heterogêneos) e revisores igualmente eficientes (homogêneos). Em seguida, sob a hipótese de heterogeneidade e independência entre erros e homogeneidade e independência entre revisores, supusemos que a heterogeneidade dos erros era expressa por uma classificação destes em fácil e difícil de detectar, admitindo conhecidas as probabilidades de detecção de um erro fácil e de um erro difícil. Finalmente, sob a hipótese de independência e homogeneidade entre erros, apresentamos um novo modelo considerando heterogeneidade e dependência entre revisores. Além disso, apresentamos exemplos com dados simulados e reais.

Il existe une grande variabilité dans la réponse aux chimiothérapies anticancéreuses. Ses sources sont diverses: génétiques, physiologiques, comorbidités, médicaments associés, etc. La marge thérapeutique de ces médicaments étant généralement étroite, une telle variabilité peut avoir de graves conséquences: toxicités graves ou absence d'effet thérapeutique. Plusieurs approches pour adapter individuellement les posologies ont été proposées: a priori (basées sur l'information génétique, la taille corporelle, les fonctions d'élimination, etc.) et a posteriori (sur les informations de mesures d'exposition au médicament et/ou effets). La modélisation à effets-mixtes de la pharmacocinétique et de la pharmacodynamie (PK-PD), combinée avec une estimation bayésienne des effets individuels, est la meilleure méthode pour individualiser des schémas posologiques a posteriori. Dans cette thèse, une nouvelle approche pour ajuster les doses sur la base des prédictions données par un modèle pour les observations catégorielles de toxicité a été développée et explorée par simulation. Les aspects plus techniques concernant l'estimation des paramètres individuels ont été analysés pour déterminer les facteurs de bonne performance de la méthode. Ces travaux étaient basés sur l'exemple du syndrome mains-pieds induit par la capécitabine dans le traitement du cancer colorectal. Une revue des modèles pharmacodynamiques de données discrètes (catégorielles, de comptage, de survie) a été effectuée. Enfin, des analyses PK-PD de l'hydroxyurée dans le traitement de la drépanocytose ont été réalisées pour comparer des différentes posologies et déterminer les modalités optimales de suivi du traitement / There is high variability in response to cancer chemotherapies among patients. Its sources are diverse: genetic, physiologic, comorbidities, concomitant medications, environment, compliance, etc. As the therapeutic window of anticancer drugs is usually narrow, such variability may have serious consequences: severe (even life-threatening) toxicities or lack of therapeutic effect. Therefore, various approaches to individually tailor treatments and dosing regimens have been developed: a priori (based on genetic information, body size, drug elimination functions, etc.) and a posteriori (that is using information of measurements of drug exposure and/or effects). Mixed-effects modelling of pharmacokinetics and pharmacodynamics (PK-PD), combined with Bayesian maximum a posteriori probability estimation of individual effects, is the method of choice for a posteriori adjustments of dosing regimens. In this thesis, a novel approach to adjust the doses on the basis of predictions, given by a model for ordered categorical observations of toxicity, was developed and investigated by computer simulations. More technical aspects concerning the estimation of individual parameters were analysed to determine the factors of good performance of the method. These works were based on the example of capecitabine-induced hand-and-foot syndrome in the treatment of colorectal cancer. Moreover, a review of pharmacodynamic models for discrete data (categorical, count, time-to-event) was performed. Finally, PK-PD analyses of hydroxyurea in the treatment of sickle cell anemia were performed and used to compare different dosing regimens and determine the optimal measures for monitoring the treatment