Passive sampling, as opposed to the conventional spot or bottle water sampling technique, has shown to be reliable and efficient in monitoring the toxicologically relevant, freely dissolved (e.g. bioavaialable) concentrations of a wide range of organic contaminants in water. At the same time, partitioning controlled delivery (passive dosing; PD) techniques promise to overcome many of the challenges associated with toxicity testing of hydrophobic substances that may bias the interpretation of toxicity data. The present study investigated the feasibility of coupling silicone rubber passive sampling devices (SR-PSDs) with bioassay techniques for both chemical and ecotoxicological assessment of complex mixtures of organic contaminants in the aquatic environment. SR-PSDs were deployed in water at various locations within the Ythan catchment (north east, Scotland, UK), Forth estuary and the Firth of Forth (east coast of central Scotland, UK) for 7 to 9 weeks. Following retrieval, extracts from the SR-PSDs were analysed for dissolved concentrations of a variety of organic contaminants including PAHs and PCBs using GC-MS and GC-ECD respectively and were screened for a wide range of pesticides using GC-MS/MS and LC-MS/MS. The extracts were further evaluated for acute cytotoxicity (i.e. neutral red uptake assay) and EROD induction potential using rainbow trout liver cell line (Oncorhynchus mykiss; RTL-W1) and for phytotoxicity and developmental toxicity potential using algal growth inhibition test (with a marine phytoplankton, Diacronema lutheri) and fish embryo toxicity test (with embryos from zebrafish Danio rerio) respectively. Overall, the individual and total dissolved concentrations of PAHs (ΣPAH40; parent and branched) and PCBs (ΣPCB32; ortho and mono-ortho) measured in water from the Ythan, Forth estuary and Firth of Forth were relatively low compared with other studies using PSDs. A number and level of pesticides, including insecticides, herbicides and fungicides of varying hydrophobicity (log KOWs ~2.25 to ~5.31) were detected in the silicone rubber (SR) extracts from the Ythan catchment, the Forth estuary and the Firth of Forth, suggesting input mainly from agricultural run-off and possibly from direct discharges. No statistically significant (p<0.05) acute cytotoxicity was observed following 48 h exposure of RTL-W1 cells to SR extracts from the Ythan catchment. But, on a sublethal level, for every site, statistically significant EROD activity was observed to some degree following 72 h exposure. In addition, developmental and algal toxicities on embryos of D. rerio and D. lutheri respectively, were measured in all the deployed samples compared with the procedural controls (undeployed samples). Interestingly, extracts of SR-PSDs from the Forth estuary and the Firth of Forth exhibited growth inhibitions on D. lutheri that were similar to those of extracts from the Ythan, even though, fewer numbers of pesticides were detected in the Forth estuary and Firth of Forth than the Ythan. This suggests that pesticides were not solely responsible for the observed effects in the Ythan catchment. To further improve data from toxicity testing of hydrophobic substances, the study identified the use of SR O-rings as a suitable passive dosing format in in vitro toxicity tests and was partially validated through their use in dosing RTL-W1 cells with two individual PAHs and subsequently determining cytotoxicity and EROD-activity.

Background: In paediatrics, the limited documentation to guide medication, the lack of suitable dosage forms, and the continuous development in childhood present a scenario where safety of medication is a particular challenge. Aim: To explore reported adverse drug reactions (ADRs) and the challenges in prescribing and administering medicines in paediatrics, in order to identify and suggest areas needing international surveillance within medication safety and improvement in the clinical setting. Methods: Four exploratory studies were conducted. Worldwide reporting of suspected ADRs (individual case safety reports, ICSR) with ages 0-17 years were examined overall. Twenty published case reports and ICSRs for adolescents, who developed a rare and incompletely documented ADR (rhabdomyolysis) during antipsychotic medicine use, were analysed in-depth. Prescribed doses of anti-inflammatory medicines were studied in a UK electronic health record database. Transcribed focus group interviews with 20 registered nurses from four paediatric wards in Sweden were analysed for factors that may promote or hinder safe medication practices. Descriptive statistics, multiple regression, and content analyses were used. Results: Although, skin reactions and anti-infective medicines were most frequently reported, and more reported in paediatric patients than in adults, medication errors and adverse reactions related to psychostimulant medicines were reported with increased frequency during 2005 to February 2010. The in-depth case analysis emphasised the need for increased vigilance following changes in patients’ medicine regimens, and indicated that ICSRs could contribute with clinically valuable information. Prescribed dose variations were associated with type of dosage form. Tablets and capsules were prescribed with a higher dose than liquid dosage forms. Six themes emerged from the interviews: preparation and administration was complex; medication errors caused considerable psychological burden; support from nurse colleagues was highly valued; unfamiliar medication was challenging; clear dose instructions were important; nurses handling medications needed to be accorded higher priority. Conclusions: Age-specific screening of ICSRs and the use of ICSRs to enhance knowledge of ADRs and medication errors need to be developed. Access to age-appropriate dosage forms is important when prescribing medicines to children. To improve medication safety practices in paediatric care, interdisciplinary collaborations across hospitals on national or even global levels are needed.

The aim of this dissertation thesis was to study the factors affecting drug distribution and elimination and to use these factors to individualize dosing. The work consists of three thematic areas: estimation of the volume of distribution and subsequent dosing of selected drugs (vancomycin, amikacin, phenobarbital) using body size descriptors; estimation of clearance and subsequent dosing of selected drugs (vancomycin, amikacin, phenobarbital, perindopril) using renal function status markers; and the impact of drug interactions on the distribution and elimination of phenobarbital. The thesis summarizes original papers on these topics. Individual pharmacokinetic parameters were calculated for each patient based on their demographic and clinical characteristics, dosing records and measured serum drug levels. The relationships between distribution volume/drug clearance and body size descriptors/renal functional status markers were examined by regression analysis. Vancomycin volume of distribution was best predicted by the total body weight. Loading dose of 10.7 mg/kg of total body weight was optimal in patients taking continuous vancomycin and would lead to reducing of median time to reach target concentrations from 17 to 1 hour. On the contrary, amikacin volume of distribution was most associated...

Problématique: En immunothérapie orale (ITO), le manque de variété et l’aversion envers les doses d’allergènes peuvent compromettre l’adhérence au traitement, toutefois essentielle pour maintenir la désensibilisation. Le but de l’étude était de développer et de valider une nouvelle intervention nutritionnelle pour l’utilisation d’options d’équivalences à domicile. Méthodes: L’intervention a été développée selon les besoins de familles déjà en ITO, exprimés lors d’entrevues préliminaires. De nouveaux patients débutant l’ITO ont ensuite été invités dans un essai contrôlé randomisé pour évaluer l’impact de l’intervention. Les participants (n = 30) ont été randomisés en 3 groupes : A) Consultation nutritionnelle avec outils d’options d’équivalences (intervention complète); B) Consultation nutritionnelle sans les outils (intervention partielle) et C) Groupe contrôle avec l’intervention complète retardée de 4 semaines. La compétence des parents pour le calcul de doses d’équivalences était suivie de façon longitudinale par une série d’exercices pratiques. Résultats: Les résultats aux exercices étaient en moyenne supérieurs avec l’intervention complète (93,3% ± 3,1), comparés au groupe contrôle sans intervention (1,7% ± 1,7, p<0,001). La compétence était maintenue 12 semaines plus tard (résultats de 88,9% ± 4,7). Sans les outils, l'acquisition initiale (résultats de 46,7% ± 7,3) et la rétention après 4 semaines (résultats de 26,7% ± 5,1) étaient inférieures, mais augmentaient après l’ajout des outils (résultats de 83,3% ± 7,5). La satisfaction et la diversité des doses ont également augmenté avec l’intervention complète. Conclusion: Cette étude démontre l'efficacité d'un programme d'intervention nutritionnelle pour accompagner la gestion des doses d'allergènes à domicile. L'utilisation de documents écrits est essentielle pour en obtenir tout le bénéfice. / Background: During oral immunotherapy (OIT), lack of palatability or diversity in daily allergen doses can compromise treatment adherence, which is essential to maintain benefit. The aim of the study was to develop and validate a nutritional intervention program on the use of whole food alternatives for allergen daily dosing during OIT. Methods: The program was initially developed based on preliminary interviews with families already on OIT. Patients beginning OIT were then invited to participate to an open-label randomized controlled trial to assess the impact of the intervention. Participants (n=30) were randomized into 3 arms when they transferred to whole foods: A) Dietitian counselling with supporting documents (full intervention); B) Dietitian counselling without document; C) Control group where full intervention was delayed by 4 weeks. Parent competency was followed longitudinally using a series of practical food dose calculation exercises. Results: Results of exercises at week 4 were in average higher in the full intervention group (93.3% ± 3.1) compared to reference group without intervention (1.7% ± 1.7, p<0.0001). Competency was maintained 12 weeks after intervention (results of 88.9% ±4.7). Without written documents, the initial acquisition (results of 46.7% ±7.3) and retention of competency at 4 weeks (results of 26.7% ±5.1) were lower, but competency was rescued by adding written documents (results of 83.3% ±7.5). Patient satisfaction and food diversity also increased with full intervention. Conclusion: This study demonstrates the efficacy of a nutritional intervention program to help patients and their parents manage their OIT allergen doses. The use of written documents is essential to achieve the full benefit.

In healthcare, vulnerable populations that are using medications with a narrow therapeutic index and wide interpatient PK/PD (pharmacokinetic/pharmacodynamic modelling) variability are increasing. As such, variable dosage regimens may result in severe therapeutic failures or adverse drug reactions (ADR). Improved monitoring of patient response to medication and personalization of treatment is therefore warranted. Precision dosing aims to individualize drug regimens for each patient based on independent factors obtained from a patient’s clinical records. Personalization of dosing increases the accuracy and efficiency of medication delivery. This can be achieved through utilizing the wide range of Electronic Health Records (EHR) contain the patients’ medical history, diagnoses, laboratory test results, demographics, treatment plans, biomarker data; information that can be exploited to generate a patient-specific treatment regimen. For example, Fast Healthcare Interoperability Resources (FHIR) is an existing healthcare standard that provides a framework on which semantic exchange of meaningful clinical information can be developed such as using an ontology as a decision support tool to achieve precision medicine. The purpose of this thesis is to make an investigation of the feasibility of interoperability in EHR and propose an ontology framework for precision dosing using currently existing health standards. The methodology involved carrying out of semi-structured interviews from professionals in relevant areas of expertise and document analysis of already existent literature, a precision dosing ontology framework is developed. Results show key tenants for an ontology framework and drugs and their covariates. The thesis therefore advances to investigate how data requirements in EHR systems, IT platforms, implementation, and integration of Model Imposed Precision Dosing (MIPD) and recommendations have been evaluated to cater to interoperability. With modern healthcare striving for personalized healthcare, precision medicine would offer an improved therapeutic experience for a patient.

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