<p>To increase the proportion of patients with successful drug treatment, dose individualisation on the basis of one or several patient characteristics, <i>a priori</i> individualisation, and/or on the basis of feedback observations from the patient following an initial dose, <i>a posteriori</i> individualisation, is an option. Efficient tools in optimising individualised dosing strategies are population models describing pharmacokinetics (PK) and the relation between pharmacokinetics and pharmacodynamics (PK/PD).</p><p>Methods for estimating optimal dosing strategies, with a discrete number of doses, for dose individualisation <i>a priori</i> and <i>a posteriori</i> were developed and explored using simulated data. The methods required definitions of (<i>i</i>) the therapeutic target, <i>i.e. </i>the value of the target variable and a risk function quantifying the seriousness of deviation from the target, (<i>ii</i>) a population PK/PD model relating dose input to the target variable in the patients to be treated, and (<i>iii</i>) distributions of relevant patient factors. Optimal dosing strategies, in terms of dose sizes and individualisation conditions, were estimated by minimising the overall risk. Factors influencing the optimal dosing strategies were identified. Consideration of those will have implications for study design, data collection, population model development and target definition.</p><p>A dosing strategy for <i>a priori</i> individualisation was estimated for NXY-059, a drug under development. Applying the estimated dosing strategy in a clinical study resulted in reasonable agreement between observed and expected outcome, supporting the developed methodology.</p><p>Estimation of a dosing strategy for <i>a posteriori</i> individualisation for oxybutynin, a drug marketed for the treatment of overactive bladder, illustrated the implementation of the method when defining the therapeutic target in terms of utility and responder probability, that is, as a combination of the desired and adverse effects.</p><p>The proposed approach provides an estimate of the maximal benefit expected from individualisation and, if individualisation is considered clinically superior, the optimal conditions for individualisation. The main application for the methods is in drug development where the methods can be generally employed in the establishment of dosing strategies for individualisation with relevant extensions regarding population model complexity and individualisation conditions.</p>

<p>Cefuroxime is a renally eliminated antibiotic used against a variety of different bacterial infections. The pharmacokinetics (PK) for cefuroxime was studied in 97 hospitalized patients using population analysis. To be able to measure cefuroxime in human serum a new sensitive analytical method was developed using mass spectrometry detection. The method was validated and shown to be sensitive and selective. Cystatin C was found to be a better covariate for cefuroxime clearance compared to the traditionally used creatinine clearance (CLcr). This relation might be useful when designing dosing strategies for cefuroxime and other renally eliminated drugs. </p><p>The time-courses of the biomarkers C-reactive protein (CRP), serum amyloid A (SAA), interleukin-6 (IL-6) and body temperature were studied for the first 72 hours of cefuroxime treatment and was related to the duration of illness previous treatment with cefuroxime and to time to step-down of treatment. When duration of illness was short, CRP and SAA were showed increasing levels. None of the biomarkers could be used to differentiate between early or late step-down of therapy.</p><p>By use of known PK and pharmacodynamic (PD) principles, dosing strategies based on CLcr for cefuroxime were estimated using minimization of a risk function. The risk function was constructed with the aim to expose patients to cefuroxime concentration above minimum inhibitory concentration (MIC) for 50 % of the dosing interval and to minimize the amount of drug administered in excess to reach the aim. Based on evaluation using wild type MIC distributions for <i>Escherichia coli</i> and <i>Streptococcus pneumoniae</i> improved dosing strategies were selected.</p><p>In vitro experiments were performed exposing <i>Streptococcus pyogenes</i> to constant concentration of benzylpenicillin, cefuroxime, erythromycin, moxifloxacin or vancomycin. A semi-mechanistic PK/PD model characterizing the time-course of the antibacterial effect was developed using all data simultaneously. Internal validation showed the model being predictive and robust. </p>

To increase the proportion of patients with successful drug treatment, dose individualisation on the basis of one or several patient characteristics, a priori individualisation, and/or on the basis of feedback observations from the patient following an initial dose, a posteriori individualisation, is an option. Efficient tools in optimising individualised dosing strategies are population models describing pharmacokinetics (PK) and the relation between pharmacokinetics and pharmacodynamics (PK/PD). Methods for estimating optimal dosing strategies, with a discrete number of doses, for dose individualisation a priori and a posteriori were developed and explored using simulated data. The methods required definitions of (i) the therapeutic target, i.e. the value of the target variable and a risk function quantifying the seriousness of deviation from the target, (ii) a population PK/PD model relating dose input to the target variable in the patients to be treated, and (iii) distributions of relevant patient factors. Optimal dosing strategies, in terms of dose sizes and individualisation conditions, were estimated by minimising the overall risk. Factors influencing the optimal dosing strategies were identified. Consideration of those will have implications for study design, data collection, population model development and target definition. A dosing strategy for a priori individualisation was estimated for NXY-059, a drug under development. Applying the estimated dosing strategy in a clinical study resulted in reasonable agreement between observed and expected outcome, supporting the developed methodology. Estimation of a dosing strategy for a posteriori individualisation for oxybutynin, a drug marketed for the treatment of overactive bladder, illustrated the implementation of the method when defining the therapeutic target in terms of utility and responder probability, that is, as a combination of the desired and adverse effects. The proposed approach provides an estimate of the maximal benefit expected from individualisation and, if individualisation is considered clinically superior, the optimal conditions for individualisation. The main application for the methods is in drug development where the methods can be generally employed in the establishment of dosing strategies for individualisation with relevant extensions regarding population model complexity and individualisation conditions.

As multidrug resistance in Gram-negative bacilli increases, the old antibiotic colistin has rapidly gained attention as one of few last line treatment options in the form of colistin methanesulfonate (CMS), which is hydrolyzed to colistin both in vitro and in vivo. There is a dearth of knowledge on fundamental aspects of colistin, including pharmacokinetics and optimal dosing regimens. The aim of this thesis was to improve the basis for optimal colistin therapy. To be able to study colistin, an LC-MS/MS assay method was developed which is sensitive, specific and useful in both in vivo and in vitro studies. Using this method we detected a significant loss of colistin during standard laboratory procedures. This loss was characterized and quantified, the hypothesis being that the loss is mainly caused by adsorption to labware. The pharmacokinetics of colistin was studied in two populations of critically ill patients, one with normal renal function and one with renal replacement therapy. Plasma concentrations were assayed with the method above, and population modeling was employed to describe the data. The results include a previously unseen, long elimination half-life of colistin. The data from the population on renal replacement therapy was described without modeling, and showed that both CMS and colistin are cleared by hemodiafiltration. Combination therapy is an approach that is often used when treating patients infected with multidrug-resistant pathogens. The thesis discusses how the joint effect of antibiotics can be measured using colistin and meropenem as a model, and proposes a method for testing antibiotic combinations. Furthermore, a PKPD model was adapted to describe the pharmacodynamics of the combination. In conclusion, a specific and sensitive method for analysis of colistin was developed and the adsorption of colistin to materials was described. The assay method has been well accepted internationally. The pharmacokinetics of colistin and CMS was described in two important patient populations, partly with surprising results that have influenced dosages of colistin worldwide. The pharmacodynamics of combination therapy was investigated and quantified, and the methods applied could be further developed into clinically useful tools for selection of antibiotic combinations.

Interactions of cells with their chemical microenvironments are critical to many polarized processes, including differentiation, migration, and pathfinding. To investigate such cellular events, tools are required that can rapidly reshape the microscopic chemical landscapes presented to cultured cells. Existing chemical dosing technologies rely on use of pre-fabricated chemical gradients, thus offering static cell-reagent interactions. Such interactions are particularly limiting for studying migration and chemotaxis, during which cells undergo rapid changes in position, morphology, and intracellular signaling. This dissertation describes the use of laminar streams, containing cellular effector molecules, for precise delivery of effectors to selected subcellular regions. In this approach, cells are grown on an ultra-thin polymer membrane that serves as a barrier to an underlying reagent reservoir. By using a tightly-focused pulsed laser beam, micron-diameter pores can be ablated in the membrane upstream of desired subcellular dosing sites. Emerging through these pores are well-defined reagent streams, which dose the targeted regions. Multiple pores can be ablated to allow parallel delivery of effector molecules to an arbitrary number of targets. Importantly, both the directionality and the composition of the reagent streams can be changed on-the-fly under a second to present dynamically changing chemical signals to cells undergoing migration. These methods are applied to study the chemotactic responses of neutrophil precursor cells. The subcellular localization of the chemical signals emerging through pores is found to influence the morphological evolution of these motile cells as they polarize and migrate in response to rapidly altered effector gradients. / text

Using seawater in cooling systems is a common practice in many parts of the world where there is a shortage of freshwater. However, biofouling is one of the major operational problems associated with the usage of seawater in cooling systems. Microfouling is caused by the activities of microorganisms, such as bacteria and algae, producing a very thin layer that sticks to the inside surface of the tubes in heat exchangers. This thin layer has a tremendously negative impact on heat transferred across the heat exchanger tubes in the system. In some instances, even a 250 micrometer thickness of fouling film can reduce the heat exchanger's heat transfer coefficient by 50 percent. On the other hand, macrofouling is the blockage caused by relatively large marine organisms, such as oysters, mussels, clams, and barnacles. A biocide is typically added to eliminate, or at least reduce, biofouling. Typically, microfouling can be controlled by intermittent dosages, and macrofouling can be controlled by continuous dosages of biocide. The aim of this research work is to develop a systematic approach to the optimal operating and design alternatives for integrated seawater cooling systems in industrial facilities. A process integration framework is used to provide a holistic approach to optimizing the design and operation of the seawater cooling system, along with the dosage and discharge systems. Optimization formulations are employed to systematize the decision-making and to reconcile the various economic, technical, and environmental aspects of the problem. Building blocks of the approach include the biocide water chemistry and kinetics, process cooling requirements, dosage scenarios and dynamic profiles, biofilm growth, seawater discharge, and environmental regulations. Seawater chemistry is studied with emphasis on the usage of biocide for seawater cooling. A multi-period optimization formulation is developed and solved to determine: * The optimal levels of dosing and dechlorination chemicals * The timing of maintenance to clean the heat-exchange * The dynamic dependence of the biofilm growth on the applied doses, the seawater-biocide chemistry, the process conditions, and seawater characteristics for each time period. The technical, economic, and environmental considerations of the system are accounted for and discussed through case studies.

Cefuroxime is a renally eliminated antibiotic used against a variety of different bacterial infections. The pharmacokinetics (PK) for cefuroxime was studied in 97 hospitalized patients using population analysis. To be able to measure cefuroxime in human serum a new sensitive analytical method was developed using mass spectrometry detection. The method was validated and shown to be sensitive and selective. Cystatin C was found to be a better covariate for cefuroxime clearance compared to the traditionally used creatinine clearance (CLcr). This relation might be useful when designing dosing strategies for cefuroxime and other renally eliminated drugs. The time-courses of the biomarkers C-reactive protein (CRP), serum amyloid A (SAA), interleukin-6 (IL-6) and body temperature were studied for the first 72 hours of cefuroxime treatment and was related to the duration of illness previous treatment with cefuroxime and to time to step-down of treatment. When duration of illness was short, CRP and SAA were showed increasing levels. None of the biomarkers could be used to differentiate between early or late step-down of therapy. By use of known PK and pharmacodynamic (PD) principles, dosing strategies based on CLcr for cefuroxime were estimated using minimization of a risk function. The risk function was constructed with the aim to expose patients to cefuroxime concentration above minimum inhibitory concentration (MIC) for 50 % of the dosing interval and to minimize the amount of drug administered in excess to reach the aim. Based on evaluation using wild type MIC distributions for Escherichia coli and Streptococcus pneumoniae improved dosing strategies were selected. In vitro experiments were performed exposing Streptococcus pyogenes to constant concentration of benzylpenicillin, cefuroxime, erythromycin, moxifloxacin or vancomycin. A semi-mechanistic PK/PD model characterizing the time-course of the antibacterial effect was developed using all data simultaneously. Internal validation showed the model being predictive and robust.

The proximity of coral reefs to coastal urban areas and shipping lanes predisposes corals to petroleum pollution from multiple sources. Previous research has evaluated petroleum toxicity to coral using a variety of methodologies, including monitoring effects of acute and chronic spills, in situ exposures, and ex situ exposures with both adult and larval stage corals. Variability in toxicant, bioassay conditions, species and other methodological disparities among studies prevents comprehensive conclusions regarding the toxicity of hydrocarbons to corals. This research evaluated the 48-hour toxicity of 1-methylnaphthalene to Porites divaricata using a continuous-flow passive dosing system. The range-finding exposure evaluated the dosing protocol and verified the effectiveness of the passive dosing technique at maintaining exposure concentrations. The full-toxicity exposures resulted in a precise estimate of toxic threshold concentrations for use in the target lipid model. The target lipid model promoted comparisons across different species by calculating the critical target lipid body burden of 355.7 µmol/ g lipid for P. divaricata. This indicates a greater resilience to petroleum hydrocarbon exposure compared to other species for which these data are available.

Class of 2016 Abstract / Objectives: The purpose of this study was to evaluate whether overweight/obese children with asthma have different systemic steroid dosing practices and asthma related readmission rates compared to normal/underweight children with asthma. Methods: Medical charts of patients admitted between October 2013 and October 2014 for an acute asthma exacerbation were reviewed retrospectively. The primary objective was to compare the average weight based systemic steroid dose between overweight/obese (Group 1) and normal/underweight (Group 2) with asthma. The secondary objective was to compare asthma-related readmissions between both groups. Data collected included demographic data; 30 day, 90 day and 6-month asthma-related readmissions; asthma medications prior-to-admission, during hospitalization and upon discharge. Results: One hundred fifty nine admissions (147 patients with recorded BMI) were evaluated. There was no significant difference in the proportion of obese, overweight, healthy and underweight patients who had 6-month asthma readmissions (p > 0.05). The mean systemic steroid, including prednisone and methylprednisolone, weight based dosing was similar between Group 1 and Group 2 (p > 0.05). Likewise, the proportion of patients with 6-month readmissions was similar in both groups (p > 0.05). Conclusions: Acute asthma exacerbation pediatric patients whom are overweight/obese were not being dosed differently to normal/underweight patients and were not at risk for increased asthma-related readmission in the following 6 months.

Bottom sediments around the world store large amounts of legacy hydrophobic organic contaminants (HOCs), forming mixtures of unknown chemical composition. Primary emissions to the environment of many HOCs have been reduced as a consequence of regulation. However, HOCs may be released from the sediments to water and biota, and there is therefore a risk of negative effects on local ecosystems. The activity of benthic organisms can enhance the sediment-to-water flux of HOCs, a process called bioturbation. Few in situ assessments of the sediment-to-water flux are available in the scientific literature, and the effect of bioturbation on the sediment-to-water flux of HOCs has not been studied in the field. Thus, there is a need to improve in situ methods for direct determination of sediments as a source of HOCs to water, and thereby include the effect of bioturbation. In Paper I, a benthic flow-through chamber was developed for environmentally realistic in situ assessments of the sediment-to-water flux. In Paper II, the sediment-to-water flux of polycyclic aromatic hydrocarbons (PAHs) was assessed using the flow-through chamber at four sites on the Swedish Baltic Sea coast. The sediments at all four sites acted as sources of PAHs to water. In the same study, potential effects of bioturbation, with an increase of the sediment-to-water flux by up to one order of magnitude, were observed at sites with bioturbating organisms. In the past, assessing the toxicity of HOCs has been challenging due to difficulties in maintaining stable exposure concentrations of the test chemical. In Paper III, a passive dosing method, where the test chemical partitions from a polymer (silicone) to the aquatic exposure medium, was developed and tested for chronic exposure. A stable exposure concentration could be maintained, and the chronic toxicity to the sediment-dwelling harpacticoid Nitocra spinipes of chronic exposure to triclosan was assessed in a 6-week population development test. In Paper IV, a passive sampling and dosing method was developed and used to assess the toxicity of an environmental chemical mixture of bioavailable sediment-associated HOCs transferred from a contaminated sediment to the laboratory-based bioassay. The passive sampling and dosing method can be used to assess the toxicity of environmental mixtures of chemicals at environmentally realistic concentrations to which ecosystems are constantly exposed. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Manuscript.</p>