I och med nuvarande och kommande lagkrav för utsläpp från tunga lastbilar finns en efterfrågan på utvecklade strategier för utsläppsminskning. För att kontrollera utsläppen av kväveoxider (NOx) används katalytisk omvandling med AdBlue (vätskeblandning av urea och vatten).  AdBlue-dropparna förångas av avgaserna eller på en förångningsyta där en väggfilm kan skapas som i sin tur kan öka risken för utfällningar av urea. Därför finns ett behov av ett reglersystem för att minimera risken för utfällning,  Målet med detta examensarbete var att skapa en bättre förståelse för hur risken för utfällning av urea kan relateras till den nuvarande kalibreringen på Scania och föreslå hur det nuvarande reglersystemet kan förbättras. Tester uppdelat i två delar genomfördes i en provcell. Först testades ureadoseringen i pulser där doseringsmängden, förångningstiden och pulsfrekvensen varierades. Därefter testades varierat avgasflöde mellan två flöden genom att ändra ramptiden.  Genom visuella inspektioner visade det sig att pulserna med urea behöver längre förångningstid än vad den aktuella kalibreringen anger. Detta för att minska risken av utfällningar. Vid dosering av urea över den stationära förångningskapaciteten skapades väggfilmen längre bort från doseringsenheten. Detta leder till mindre effektiv användning av den doserade urean. För varierat avgasflöde med de valda ramptidena förändrades inte risken för utfällning. Därför skulle det nuvarande styrsystemet kunna förbättras genom att inkludera en längre tid för förångning mellan ureadoseringspulserna. / With current and upcoming emission legislation for heavy-duty transport, there is a demand for improved emission abatement strategies. To control nitrogen oxide (NOx) emissions, catalytic conversion with AdBlue (a liquid mixture of urea and water) is used. Droplets of AdBlue are evaporated by the exhaust gas or on an evaporation surface where a wall film can be created. A wall film increases the urea deposit risk which in turn causes problems. Consequently, there is a need for a control system to minimize the risk of urea deposits. The target of this thesis was to create a better understanding of how the urea deposit risk can be related to the current control calibration at Scania and to suggest how the current control system could be improved. Tests were performed in an engine testbed, in two parts. Firstly, varying of urea dosing was tested in pulses where the dosing amount, evaporation time and pulse frequency were varied. Secondly, the exhaust flow rate was varied between two flows by changing the ramp time. Through visual inspections, it was shown that the urea dosing pulses need longer evaporation time than the current control calibration states, to reduce the build-up of urea deposits. Furthermore, when dosing urea above the stationary evaporation capacity, the wall film was created further away from the dosing unit, thus, leading to less efficient use of the injected urea. For varying exhaust flow rate, the chosen ramp times did not change the urea deposit risk. Therefore, the current control system could be improved by including longer time for evaporation between the urea injection pulses.

This thesis in the field of microdata analysis aims to introduce dose optimizing algorithms for the pharmacological management of Parkinson’s disease (PD). PD is a neurodegenerative disease that mostly affects the motor functions of the patients and it is characterized as a movement disorder. The core symptoms of PD are: bradykinesia, postural instability, rigidity, and tremor. There is no cure for PD and the use of levodopa to manage the core symptoms is considered the gold standard. However, long term use of levodopa causes reduced medication efficacy, and side effects, such as dyskinesia, which can also be attributed to overmedication. When that happens precise individualized dosing schedules are required. The goal of this thesis is to examine if algorithmic methods can be used to find dosing schedules that treat PD symptoms and minimize manifestation of side effects. Data from three different sources were used for that purpose: data from a clinical study in Uppsala University hospital in 2015, patient admission chart data from Uppsala University hospital during 2011-2015, and data from a clinical study in Gothenburg University during 2016-2017. The data were used to develop the methods and evaluate the performance of the proposed algorithms.The first algorithm that was developed was a sensor-based method that derives objective measurements (ratings) of PD motor states. The construction of the sensor index was based on subjective ratings of patients’ motor functions made by three movement disorder experts. This sensor-based method was used when deriving algorithmic dosing schedules. Afterwards, a method that uses medication information and ratings of the patients’ motor states to fit individual patient models was developed. This method uses mathematical optimization to individualize specific parameters of dose-effects models for levodopa intake, through minimizing the distance between motor state ratings and dose-effect curves. Finally, two different dose optimization algorithms were developed and evaluated, that had as input the individual patient models. The first algorithm was specific to continuous infusion of levodopa treatment, where the patient’s state was set to a specific target value and the algorithm made dosing adjustments to keep that patients motor functions on that state. The second algorithm concerned oral administration of microtables of levodopa. The ambition with this algorithm was that the suggested doses would find the right balance between treating the core symptoms of PD and, at the same time, minimizing the side effects of long term levodopa use, mainly dyskinesia. Motor state ratings for this study were obtained through the sensor index. Both algorithms followed a principle of deriving a morning dose and a maintenance dose for the patients, with maintenance dose being an infusion rate for the first algorithm, and oral administration doses at specific time points for the second algorithm.The results showed that the sensor-based index had good test-retest reliability, sensitivity to levodopa treatment, and ability to make predictions in unseen parts of the dataset. The dosing algorithm for continuous infusion of levodopa had a good ability to suggest an optimal infusion rating for the patients, but consistently suggested lower morning dose than what the treating personnel prescribed. The dosing algorithm for oral administration of levodopa showed great agreement with the treating personnel’s prescriptions, both in terms of morning and maintenance dose. Moreover, when evaluating the oral medication algorithm, it was clear that the sensor index ratings could be used for building patient specific models.

Para efetivamente tratar uma infecção, é necessário que o antibiótico possua atividade antimicrobiana adequada e seja capaz de inibir o crescimento do microrganismo patogênico. O doseamento microbiológico é uma metodologia indicada para a análise do antimicrobiano de forma simples, quando comparado com outras metodologias. A Food and Drug Administration (FDA) tem encorajado uma abordagem proativa para introduzir inovações e benefícios associados ao processo de produção farmacêutica. A Qualidade por Design Analítico (AQbD) ajuda no desenvolvimento de métodos analíticos robustos e de baixo custo, que são aplicáveis durante todo ciclo de vida do produto. Os métodos microbiológicos tradicionais, de forma geral, apresentam baixa reprodutibilidade e alta incerteza. Desta forma, justifica-se o desenvolvimento de métodos microbiológicos alternativos para a análise de antimicrobianos empregando-se os conceitos de Qualidade por Design Analítico, com a finalidade de melhorar a reprodutibilidade e reduzir a incerteza final. O objetivo deste trabalho foi aplicar o conceito de Qualidade por Design Analítico (AQbD) no desenvolvimento de método colorimétrico para análise de sulfato de neomicina. O sulfato de neomicina é um antimicrobiano aminoglicosídeo amplamente empregado no tratamento de infecções cutâneas ou mucosas, tais como queimaduras, úlceras, e dermatites infecciosas. Métodos cromatográficos como a cromatografia líquida de alta eficiência em fase reversa, de pareamento iônico ou cromatografia iônica com derivatização (pré ou pós-coluna) são utilizados para a análise de aminoglicosídeos, inclusive sulfato de neomicina. Contudo, de acordo com as farmacopeias, o método microbiológico é o método analítico de escolha para a análise de sulfato de neomicina e outros aminoglicosídeos. A análise colorimétrica é um método amplamente utilizado para a detecção e quantificação de diferentes substâncias, incluindo o crescimento microbiano em estudos de eficácia terapêutica. Neste trabalho, propomos o uso de resazurina como marcador colorimétrico. O indicador sofre uma reação de oxido-redução na qual altera a coloração em resposta à redução química resultante do crescimento celular. O uso de microplacas para a análise colorimétrica é uma alternativa ao método realizado em tubos de ensaio. Uma alternativa ao uso de espectrofotômetros para a análise colorimétrica é o uso de aparelhos smartphones, pois são equipados com CPUs rápidas, câmeras de alta resolução e sensores de imagem. O processamento da imagem captada pela câmera do dispositivo é utilizado como um analisador colorimétrico. Portanto, a aplicação dos conceitos de Qualidade por Design Analítico (AQbD) possibilitou o desenvolvimento racional de método microbiológico colorimétrico para análise de sulfato de neomicina. / To effectively treat an infection, the antibiotic must have adequate antimicrobial activity and be capable of inhibiting the growth of the pathogenic microorganism. The microbiological assay is an indicated methodology for the analysis of the antimicrobial in a simple way, when compared with other methodologies. The Food and Drug Administration (FDA) has encouraged a proactive approach to introducing innovations and benefits associated with the pharmaceutical production process. Analytical Design Quality (AQbD) assists in the development of robust, low cost analytical methods that are applicable throughout the product life cycle. Traditional microbiological methods, in general, have low reproducibility and high uncertainty. Thus, it is justified the development of alternative microbiological methods for the analysis of antimicrobials using the concepts of Quality by Analytical Design, in order to improve reproducibility and reduce final uncertainty. The objective of this work was to apply the concept of Quality by Analytical Design (AQbD) in the development of a colorimetric method for the analysis of neomycin sulfate. Neomycin Sulfate is an aminoglycoside antimicrobial widely used in the treatment of cutaneous or mucosal infections, such as burns, ulcers, and infectious dermatitis. Chromatographic methods such as reverse phase high performance liquid chromatography, ion-pairing or ion chromatography with derivatization (pre or post-column) are used for the analysis of aminoglycosides, including neomycin sulfate. However, according to pharmacopoeias, the microbiological method is the analytical method of choice for the analysis of neomycin sulphate and other aminoglycosides. Colorimetric analysis is a widely used method for the detection and quantification of different substances, including microbial growth in studies of therapeutic efficacy. In this work, we propose the use of resazurin as a colorimetric marker. The indicator undergoes an oxidation-reduction reaction in which it alters the coloration in response to the chemical reduction resulting from cell growth. The use of microplates for colorimetric analysis is an alternative to the method carried out in test tubes. An alternative to the use of spectrophotometers for colorimetric analysis is the use of smartphones because they are equipped with fast CPUs, high resolution cameras and image sensors. The image processing captured by the device\'s camera is used as a colorimetric analyzer. Therefore, the application of the concepts of Quality by Analytical Design (AQbD) allowed the rational development of a microbiological colorimetric method for analysis of neomycin sulfate.

A papaína é uma enzima utilizada em formulações tópicas como agente proteolítico debridante, no tratamento de lesões abertas de grande extensão e queimaduras. Também empregada como agente promotor da permeação cutânea, peeling químico e como agente depilatório progressivo. A estabilidade de formulações contendo enzimas não é facilmente alcançada. No presente trabalho realizou-se a modificação da papaína com polietilenoglicol, visando maior estabilidade. O Teste de Estabilidade Normal de formulações cosméticas incorporadas de papaína não modificada e modificada apresentou um perfil diferenciado para a atividade da enzima modificada, nas diferentes condições de temperatura (5 ± 1 °C; 22 ± 2 °C, 40 ± 2 °C), sendo que a mais adequada para a papaína não modificada foi de 5 ± 1 °C e para a modificada foi de 22 ± 2,0 °C. Estes resultados confirmam o aumento da estabilidade da papaína modificada e o seu potencial de aplicação em formulações de uso tópico. / Papain is an enzyme used in formulations for local application as proteolitic debridant agent, treatment of wound exposed in large extension and burns. It is also applied as promotor agent of cutaneous permeation, chemical peeling and as progressive depilatory agent. The stability of formulations with enzymes is not easily obtained. In this work modification of papain with polyethylenglycol was made in order to obtain more stability. The Test of Normal Stability of cosmetic formulations incorporated with papain not-modified and modified, showed a differentiated profile for modified enzyme in different conditions of temperature (5 ± 1 °C; 22 ± 2 °C, 40 ± 2 °C), being that, the most adequated for papain not-modified was 5 ± 1°C and for modified was 22 ± 2,0 °C. These results confirm the increase of stability of papain modified and its potential application in formulations for local application.

Submitted by Eunice Novais (enovais@uepg.br) on 2018-08-22T18:09:08Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Ricardo Dalacort.pdf: 1861957 bytes, checksum: 5c11f28e6c7ce7d5d7a7923c738f61c9 (MD5) / Made available in DSpace on 2018-08-22T18:09:08Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Ricardo Dalacort.pdf: 1861957 bytes, checksum: 5c11f28e6c7ce7d5d7a7923c738f61c9 (MD5) Previous issue date: 2018-06-19 / A agricultura moderna utiliza-se de técnicas e tecnologias que possibilitam o aumento da produtividade e possível redução dos custos ao produtor. Otimizar o uso de insumos aplicando dosagens exatas e precisas, condizentes com as reais necessidades do solo, além de proporcionar os nutrientes necessários para o correto desenvolvimento das culturas, possibilita reduzir os custos e impactos ambientais causados pelo uso incorreto de produtos como fertilizantes e agrotóxicos. A eficiência na produtividade de um sistema depende principalmente das tecnologias empregada a ela, e que, por sua vez, seu bom aproveitamento depende da quantidade de informação disponível para melhor aplicabilidade de seus recursos. O principal objetivo desse trabalho foi desenvolver empiricamente um sensor capacitivo para identificar ausência, presença e variações na distribuição de fertilizante minerais sólidos. O sensor desenvolvido identificou em todos os testes realizados, a ausência ou a presença de fertilizantes independente da formulação testada, apresentando coeficiente de variação inferior a 10% representando homogeneidade e baixa dispersão dos dados em relação à média aritmética. Os maiores erros expressos pelo desvio padrão – DVP ocorreram em estado dinâmico com a formulação 06-21-12 apresentando valores de 6,19 pF e 7,14 pF para o mecanismo dosador por gravidade e por transbordo respectivamente. Na identificação de variações da distribuição do fertilizante, o sensor identificou a redução do fluxo do fertilizante em todos os experimentos quando a obstrução foi imposta. Para a formulação 00-00-60 a redução da capacitância foi de aproximadamente 55% para o mecanismo dosador por gravidade e de 58% para o mecanismo dosador por transbordo. As demais formulações apresentaram variações próximas a estas na imposição da obstrução. Na análise relacionada a identificação da formulação de fertilizante, apenas as formulações 02-28-20 e 06-21-12 nos experimentos realizados com o mecanismo dosador por transbordo não se diferem estatisticamente entre si, sendo que todas as demais formulações apresentaram diferença estatisticamente significante pela analise ANOVA e pelo Teste de Tukey a 5% de significância. A umidade teve influência na permissividade dielétrica das formulações de fertilizantes testadas 02-20-10 e 02-28-20, gerando alterações na resposta do sensor, sendo mais expressiva em níveis de umidade de 6,33% e 7,56% respectivamente, apresentando aumento da capacitância em 493,60% e 385,51% em relação as umidades iniciais de 1,66% e 2%. / Modern agriculture uses techniques and technologies that allow the increase of productivity and possible reduction of costs to the producer. Optimizing the use of inputs by applying precise and precise dosages, in keeping with the real needs of the soil, besides providing the necessary nutrients for the correct development of the crops, reduces the costs and environmental impacts caused by the incorrect use of products such as fertilizers and agrochemicals. The productivity efficiency of a system depends mainly on the technology that is used to it, and that, in turn, its good use depends on the amount of information available to better apply its resources. The main objective of this work was to develop empirically a capacitive sensor to identify absence, presence and variations in the distribution of solid mineral fertilizer. The developed sensor identified in all tests the absence or presence of fertilizers independent of the tested formulation, presenting a coefficient of variation of less than 10% representing homogeneity and low dispersion of the data in relation to the arithmetic mean. The highest errors expressed by the standard deviation - DVP occurred in dynamic state with the formulation 06-21-12 presenting values of 6.19 pF and 7.14 pF for the gravity and overflow mechanism respectively. In the identification of variations of the fertilizer distribution, the sensor identified the reduction of fertilizer flow in all experiments when the obstruction was imposed. For the formulation 00-00-60 the capacitance reduction was approximately 55% for the gravity loading mechanism and 58% for the transhipment dosing mechanism. The other formulations presented variations close to these. In the analysis related to the identification of the fertilizer formulation, only formulations 02-28-20 and 06-21-12 in the experiments performed with the transhipment dosing mechanism do not differ statistically from each other, and all other formulations presented a statistically significant difference by ANOVA and Tukey's test at 5% significance. Moisture had an influence on the dielectric permittivity of the tested fertilizer formulations 02-20-10 and 02-28-20, generating alterations in the sensor response, being more expressive in humidity levels of 6.33% and 7.56%, respectively, presenting capacitance increase in 493.60% and 385.51% in relation to the initial humidities of 1.66% and 2%.

Submitted by ANDRÉ FERREIRA DAMASCENO null (andrefdamasceno@gmail.com) on 2017-03-14T23:13:40Z No. of bitstreams: 1 Dissertacao_Andre_Ferreira_Damasceno.pdf: 1505015 bytes, checksum: 5579bcda03f23c5ff90ef330bc419303 (MD5) / Approved for entry into archive by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br) on 2017-03-20T22:58:22Z (GMT) No. of bitstreams: 1 damasceno_af_me_jabo.pdf: 1505015 bytes, checksum: 5579bcda03f23c5ff90ef330bc419303 (MD5) / Made available in DSpace on 2017-03-20T22:58:22Z (GMT). No. of bitstreams: 1 damasceno_af_me_jabo.pdf: 1505015 bytes, checksum: 5579bcda03f23c5ff90ef330bc419303 (MD5) Previous issue date: 2017-02-24 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A velocidade de trabalho na operação de semeadura é um fator que pode influenciar na regularidade de distribuição de sementes, e, sendo assim, o sistema dosador de sementes deve ser capaz suprir tal discordância, mantendo a qualidade e precisão de operação elevadas. Portanto, objetivou-se avaliar a qualidade de operação e possíveis influências dos sistemas dosador de sementes (acionamento e dosagem), operando em diferentes velocidades de operação, na operação de semeadura direta de soja. O delineamento experimental foi em faixas, fatorial 4x2, com dosadores pneumáticos, com acionamento hidráulico e elétrico, e dosadores mecânicos acionados por corrente (mecânico), e velocidades teóricas de deslocamento de 6 e 9 km h-1. As variáveis avaliadas foram: densidade de semeadura, distribuição longitudinal de plântulas, profundidade de semeadura e produtividade. Aplicou-se estatística descritiva e os resultados foram submetidos ao teste F (5%), e teste para comparação de médias quando necessário, e através do controle estatístico de processos (CEP), com a ferramenta de cartas de controle de valores individuais e amplitude média, pode-se mensurar a qualidade do processo em cada arranjo. De maneira geral, o dosador pneumático com acionamento hidráulico e a velocidade de 6 km h-1 apresentaram melhores resultados para densidade de semeadura, espaçamentos aceitáveis e produtividade. O incremento da velocidade reduz os espaçamentos aceitáveis e produtividade. Espaçamentos múltiplos e profundidade de semeadura não influenciaram os fatores estudados. Os dosadores pneumáticos operando a velocidade de 6 km h-1 apresentaram menor variabilidade e pontos dentro dos limites de controle, indicando maior qualidade de operação. / The working speed in the sowing operation is a factor that can influence the regularity of seed distribution, and, thus, the seed feeders system must be able to supply such disagreement, maintaining high quality and high operating precision. The objective of this study was to evaluate the quality of operation and possible influences of the seed dosing systems (activation and dosing), operating at different speeds of operation, in the direct sowing of soybean. The experimental design was in bands, factorial 4x2, with pneumatic dosers with hydraulic and electric activation systems, and mechanical actuators (mechanical), and theoretical displacement speeds of 6 and 9 km h-1. The evaluated variables were: sowing density, longitudinal distribution of seedlings, depth of sowing and productivity. Descriptive statistics were applied and the results were submitted to the F test (5%), and test for comparison of means when necessary, and through the statistical control of processes (CEP), with the tool of control charts of individual values and amplitude average, one can measure the quality of the process in each arrangement. In general, the pneumatic doser with hydraulic activator and the speed of 6 km h-1 presented better results for sowing density, acceptable spacings and productivity. Increasing speed reduces acceptable spacings and productivity. Multiple spacings and depth of sowing had no influence on the factors studied. The pneumatic dosers operating at a speed of 6 km h-1 presented lower variability and points within the control limits, indicating a higher quality of operation.

<p>Antibiotic treatment causes an ecological disturbance on the human microflora. Four commensal bacteria: E. coli, enterococci, a-streptococci and coagulase-negative staphylococci, from patients with extensive, high antibiotic usage were investigated with regard to resistance pattern and mutation frequency. Among 193 investigated strains it was found that high antibiotic usage selected for resistant bacteria and enriched for bacteria with a small but significantly increased mutation frequency. </p><p>The relative biological fitness cost of resistance in <i>Staphylococcus epidermidis</i> was assessed in a human in vivo model where the indigenous flora was present. In vitro data of the bacterial growth rate correlated well to in vivo fitness assayed in the competition experiments on skin. </p><p>An in vitro kinetic model was shown to be a useful tool to establish the pharmacokinetic and pharmacodynamic (PK/PD) indices for efficacy of antibiotics. It was confirmed that the time, when the concentration exceeds the minimal inhibitory concentration (MIC), correlates with efficacy for b-lactam antibiotics. To achieve maximal killing for penicillin-resistant pneumococci, with an MIC of 2 mg/L, the peak concentration was also of importance. </p><p>Suboptimal dosing regimen facilitates selection of resistance. Penicillin-resistant pneumococci were easily selected in a mixed population with penicillin-sensitive, -intermediate and -resistant pneumococci in an in vitro kinetic model. The selection of the resistant strain was prevented when the benzylpenicillin concentration exceeded the MIC for approximately 50% of 24 h.</p>

<p>Standard dosing of chemotherapy based on body surface area (BSA) results in large individual differences in toxicity due to a large inter-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD). This results in under-dosing in certain patients with a potentially weaker antitumoral effect.</p><p>Three clinical studies of individually tailored dosing of chemotherapy, based on haematological toxicity were conducted. In the first study, 26 women with metastatic breast cancer were treated with tailored and dose-escalated 5-fluorouracil, epirubicin and cyclophosphamide, supported by G-CSF (dFEC). In the second study 525 patients with high-risk primary breast cancer were randomised between dFEC and high-dose chemotherapy with autologous bone-marrow transplantation. The feasibility of a FEC regimen with doubled cyclophosphamide dose to mobilise peripheral stem cells was investigated. In the third study, 44 metastatic patients were treated with tailored epirubicin and docetaxel (ET). PK and PD were also investigated in these patients. The potential effects of G-CSF on MRI tumour evaluation were studied in 18 patients with skeletal metastases.</p><p>Toxicity-based dosing entailed an evenly distributed two- to three-fold range of tolerated doses in all three studies. Efficacy and toxicity were not correlated to tolerated dose-levels. Tailored dFEC resulted in a response rate of 81% and the same regimen resulted in fewer breast cancer relapses compared with standard FEC followed by high-dose therapy. Toxicity was manageable except for an increased rate of secondary leukaemia. The modified FEC could safely mobilise sufficient numbers of stem-cells. Tailored ET resulted in a response rate of 63%. The inter-individual variability in drug clearance was larger than the inter-occasion variability and a semi-physiological model of PK and PD could predict leukocyte nadir and duration. An increased diffuse MR signal in the long TE IR-TSE sequence was observed in normal bone-marrow during G-CSF treatment; this could be mistaken as disseminated metastatic disease and could obscure focal metastases.</p><p>In conclusion, the concept of individually tailored toxicity-based dosage of chemotherapy was equally feasible in primary and metastatic breast cancer, in two different chemotherapy regimens and in treatment with or without G-CSF support and may provide a pragmatic way of overcoming the shortcomings of standard BSA-based dosing.</p>

Standard dosing of chemotherapy based on body surface area (BSA) results in large individual differences in toxicity due to a large inter-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD). This results in under-dosing in certain patients with a potentially weaker antitumoral effect. Three clinical studies of individually tailored dosing of chemotherapy, based on haematological toxicity were conducted. In the first study, 26 women with metastatic breast cancer were treated with tailored and dose-escalated 5-fluorouracil, epirubicin and cyclophosphamide, supported by G-CSF (dFEC). In the second study 525 patients with high-risk primary breast cancer were randomised between dFEC and high-dose chemotherapy with autologous bone-marrow transplantation. The feasibility of a FEC regimen with doubled cyclophosphamide dose to mobilise peripheral stem cells was investigated. In the third study, 44 metastatic patients were treated with tailored epirubicin and docetaxel (ET). PK and PD were also investigated in these patients. The potential effects of G-CSF on MRI tumour evaluation were studied in 18 patients with skeletal metastases. Toxicity-based dosing entailed an evenly distributed two- to three-fold range of tolerated doses in all three studies. Efficacy and toxicity were not correlated to tolerated dose-levels. Tailored dFEC resulted in a response rate of 81% and the same regimen resulted in fewer breast cancer relapses compared with standard FEC followed by high-dose therapy. Toxicity was manageable except for an increased rate of secondary leukaemia. The modified FEC could safely mobilise sufficient numbers of stem-cells. Tailored ET resulted in a response rate of 63%. The inter-individual variability in drug clearance was larger than the inter-occasion variability and a semi-physiological model of PK and PD could predict leukocyte nadir and duration. An increased diffuse MR signal in the long TE IR-TSE sequence was observed in normal bone-marrow during G-CSF treatment; this could be mistaken as disseminated metastatic disease and could obscure focal metastases. In conclusion, the concept of individually tailored toxicity-based dosage of chemotherapy was equally feasible in primary and metastatic breast cancer, in two different chemotherapy regimens and in treatment with or without G-CSF support and may provide a pragmatic way of overcoming the shortcomings of standard BSA-based dosing.

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