<p>Pharmacometric modelling is an increasingly used method for analysing the outcome from clinical trials in drug development. The model building process is complex and involves testing, evaluating and diagnosing a range of plausible models aiming to make an adequate inference from the observed data and predictions for future studies and therapy. </p><p>The aim of this thesis was to advance the approaches used in pharmacometrics by introducing improved models and methods for application in essential parts of model building procedure: (i) structural model development, (ii) stochastic model development and (iii) model diagnostics. </p><p>As a contribution to the structural model development, a novel flexible structural model for drug absorption, a transit compartment model, was introduced and evaluated. This model is capable of describing various drug absorption profiles and yet simple enough to be estimable from data available from a typical trial. As a contribution to the stochastic model development, three novel methods for parameter distribution estimation were developed and evaluated; a default NONMEM nonparametric method, an extended grid method and a semiparametric method with estimated shape parameters. All these methods are useful in circumstances when standard assumptions of parameter distributions in the population do not hold. The new methods provide less biased parameter estimates, better description of variability and better simulation properties of the model. As a contribution to model diagnostics, the most commonly used diagnostics were evaluated for their usefulness. In particular, diagnostics based on individual parameter estimates were systematically investigated and circumstances which are likely to misguide modelers towards making erroneous decisions in model development, relating to choice of structural, covariate and stochastic model components were identified. </p><p>In conclusion, novel approaches, insights and models have been provided to the pharmacometrics community. </p><p>Implementation of these advances to make model building more efficient and robust has been facilitated by development of diagnostic tools and automated routines.</p>

Pharmacometric modelling is an increasingly used method for analysing the outcome from clinical trials in drug development. The model building process is complex and involves testing, evaluating and diagnosing a range of plausible models aiming to make an adequate inference from the observed data and predictions for future studies and therapy. The aim of this thesis was to advance the approaches used in pharmacometrics by introducing improved models and methods for application in essential parts of model building procedure: (i) structural model development, (ii) stochastic model development and (iii) model diagnostics. As a contribution to the structural model development, a novel flexible structural model for drug absorption, a transit compartment model, was introduced and evaluated. This model is capable of describing various drug absorption profiles and yet simple enough to be estimable from data available from a typical trial. As a contribution to the stochastic model development, three novel methods for parameter distribution estimation were developed and evaluated; a default NONMEM nonparametric method, an extended grid method and a semiparametric method with estimated shape parameters. All these methods are useful in circumstances when standard assumptions of parameter distributions in the population do not hold. The new methods provide less biased parameter estimates, better description of variability and better simulation properties of the model. As a contribution to model diagnostics, the most commonly used diagnostics were evaluated for their usefulness. In particular, diagnostics based on individual parameter estimates were systematically investigated and circumstances which are likely to misguide modelers towards making erroneous decisions in model development, relating to choice of structural, covariate and stochastic model components were identified. In conclusion, novel approaches, insights and models have been provided to the pharmacometrics community. Implementation of these advances to make model building more efficient and robust has been facilitated by development of diagnostic tools and automated routines.

Submitted by Pedro Silva Filho (pfsilva@ipen.br) on 2017-11-21T11:35:55Z No. of bitstreams: 0 / Made available in DSpace on 2017-11-21T11:35:56Z (GMT). No. of bitstreams: 0 / Os projetos de carrocerias veiculares atuais procuram desenvolver estruturas leves, seja para reduzir o consumo de combustível, no caso dos motores de combustão interna, seja para maior autonomia de bateria, no caso dos veículos elétricos e híbridos. Redução no consumo de combustível significa redução na emissão de poluentes. As estruturas precisam ser leves, mas cada vez mais resistentes e rígidas a fim de proporcionar máximo conforto e segurança aos ocupantes. Estas premissas têm levado ao contínuo desenvolvimento dos materiais. No caso dos aços, um dos processos que tem permitido a melhora significativa das propriedades mecânicas é a estampagem a quente. Nos últimos anos, as peças estampadas a quente têm ocupado lugar de destaque na estrutura das carrocerias veiculares por estarem em sintonia com as demandas mencionadas. Há muitas pesquisas em curso para esta tecnologia, seja nos materiais, nos meios de produção, nos revestimentos e em aplicações. O aço mais utilizado neste processo, 22MnB5, também apresenta o chamado efeito bake hardening; a tensão de escoamento é aumentada após tratamento térmico realizado em temperaturas próximas a 200 °C. Neste trabalho, visando à melhoria nas propriedades mecânicas, amostras foram tratadas termicamente na faixa de temperatura supracitada. Após isso, dados obtidos de ensaios mecânicos foram inseridos em programas de simulação de impacto lateral cujo resultado foi a redução na intrusão na célula de sobrevivência. O efeito bake hardening também propiciou um aumento na absorção da energia de impacto em teste estático feito com barras de proteção lateral. O mecanismo metalúrgico envolvido no fenômeno, devido à difusão de intersticiais foi evidenciado no ensaio de atrito interno. / Tese (Doutorado em Tecnologia Nuclear) / IPEN/T / Instituto de Pesquisas Energéticas e Nucleares - IPEN-CNEN/SP