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Using Pharmacokinetic and Pharmacodynamic Principles to Evaluate Individualisation of Antibiotic Dosing – Emphasis on CefuroximeViberg, Anders January 2006 (has links)
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.
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Mechanism-Based Pharmacokinetic and Pharmacodynamic Modelling of PaclitaxelHenningsson, Anja January 2005 (has links)
Paclitaxel (Taxol®) is now widely used against breast, ovarian and non-small-cell lung cancer. Anticancer agents generally have narrow therapeutic indices, often with myelosuppression (mainly neutropenia) as dose-limiting side effect. A further complicating factor is that paclitaxel when given as Taxol® has a nonlinear pharmacokinetic (PK) behaviour in plasma. Identifying risk groups more sensitive to chemotherapy due to either a PK or pharmacodynamic (PD) interindividual variability is of importance. The aim of the thesis was to develop predictive mechanism-based PK and PD models applicable for paclitaxel. PK and PK/PD models were developed for patient data from studies with relatively frequent sampling or sparse sampling schedules. Population analyses were performed using the software NONMEM. A pharmacokinetic model describing unbound, total plasma and blood concentrations of paclitaxel from known binding mechanisms was developed and validated. The nonlinear PK in plasma could to a large extent be explained by the micelle forming vehicle Cremophor EL (CrEL) and the unbound drug showed linear PK. Besides a binding component directly proportional to concentrations of CrEL, the model included both linear and nonlinear binding components in plasma and blood. Further, relations between the PK parameters and different demographic factors, including polymorphisms in the cytochrome P450s involved in paclitaxel metabolism, were investigated. A semi-physiological PD model for chemotherapy-induced myelosuppression was developed and applied to different anticancer drugs. The model included a self-renewal for proliferating cells, transit compartments describing the delay in observed myelosuppression and a feedback parameter reflecting the effect on the bone marrow from growth factors that can result in an overshoot in white blood cells. The system-related parameters estimated showed consistency across drugs and the difference in the drug-related parameter reflected the relative bone marrow toxicity of the drugs. Relations between demographic factors and the PD parameters were identified. The developed mechanism-based models promote a better understanding of paclitaxel PK and PD and may be used as tools in dosing individualisation and in development of dosing strategies for new administration forms and new drugs in the same area.
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A study on pharmacokinetic and pharmacodynamic effects of salbutamol-isomers /Naidu Sjöswärd, Kerstin January 1900 (has links) (PDF)
Diss. (sammanfattning) Linköping : Univ., 2003. / Härtill 4 uppsatser.
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From achiral to chiral analysis of citalopram /Carlsson, Björn, January 2003 (has links)
Diss. (sammanfattning) Linköping : Univ., 2003. / Härtill 4 uppsatser.
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Pharmacokinetics and pharmacodynamics of oxycodone and morphine with emphasis on blood-brain barrier transport /Boström, Emma, January 2007 (has links)
Diss. (sammanfattning) Uppsala : Uppsala universitet, 2007. / Härtill 4 uppsatser.
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Analys av tidigare studier för utveckling av tuberkulosläkemedelPhromson, Prakasit January 2021 (has links)
Bakgrund: Tuberkulos är idag världens ledande dödsorsak. Behandlingar förlitar sig på flera kombinationer av antibiotika som har funnits i närmare 40 år. Medan tuberkulosspridningen och antibiotikaresistensen ökar förblir dagens första linje antituberkulosläkemedel oförändrade. Det är angeläget att identifiera nya läkemedel för att förbättra dagens långdragna behandlingsdurationer och motverka resistensutvecklingen. Syfte: Analysera studier som tidigare genomförts för utveckling av antituberkulosläkemedel under fas IIa, med avseende på val av biomarkör, behandlingsdesign och läkemedel. Metod: En systematisk litteraturstudie har utförts med hjälp av databaserna PubMed och Web of Science. De artiklar som inkluderades utgjordes av kliniska fas IIa studier där antituberkulosläkemedel undersöktes i early bactericidal activity (EBA) studier. Resultat: 26 studier granskades, 18 utfördes med monoterapi, 3 med kombinationsbehandling och 5 använde sig av båda behandlingsdesignerna. 15 studier pågick i två veckor, 5 i fem dagar, 5 andra i sju dagar och 1 studie pågick i två dagar. De två läkemedel som undersöktes mest frekvent var rifampicin och isoniazid. SQ109 och AZD5847 undersöktes i enstaka studier. Den mest använda biomarkören var colony forming units (CFU) som använts i samtliga studier. Biomarkören time-to-positivity (TTP) användes parallellt i 13 studier. Slutsats: För bestämning av EBA i kliniska fas IIa studier har CFU använts i samtliga, medan TTP enbart har använts i kombination med CFU. Behandlingsdesignen utgörs till största del av monoterapier där rifampicin och isoniazid har studerats mest frekvent.
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Models for Ordered Categorical Pharmacodynamic DataZingmark, Per-Henrik January 2005 (has links)
<p>In drug development clinical trials are designed to investigate whether a new treatment is safe and has the desired effect on the disease in the target patient population. Categorical endpoints, for example different ranking scales or grading of adverse events, are commonly used to measure effects in the trials. </p><p>Pharmacokinetic/Pharmacodynamic (PK/PD) models are used to describe the plasma concentration of a drug over time and its relationship to the effect studied. The models are utilized both in drug development and in discussions with drug regulating authorities. Methods for incorporation of ordered categorical data in PK/PD models were studied using a non-linear mixed effects modelling approach as implemented in the software NONMEM. The traditionally used proportional odds model was used for analysis of a 6-grade sedation scale in acute stroke patients and for analysis of a T-cell receptor expression in patients with Multiple Sclerosis, where the results also were compared with an analysis of the data on a continuous scale. Modifications of the proportional odds model were developed to enable analysis of a spontaneously reported side-effect and to analyze situations where the scale used is heterogeneous or where the drug affects the different scores in the scale in a non-proportional way. The new models were compared with the proportional odds model and were shown to give better predictive performances in the analyzed situations. </p><p>The results in this thesis show that categorical data obtained in clinical trials with different design and different categorical endpoints successfully can be incorporated in PK/PD models. The models developed can also be applied to analyses of other ordered categorical scales than those presented.</p>
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Imaging and Quantification of Brain Serotonergic Activity using PETLundquist, Pinelopi January 2006 (has links)
<p>This thesis investigates the potential of using positron emission tomography (PET) to study the biosynthesis and release of serotonin (5HT) at the brain serotonergic neuron. As PET requires probe compounds with specific attributes to enable imaging and quantification of biological processes, emphasis was placed on the evaluation of these attributes. </p><p>The experiments established that the 5HT transporter radioligand [<sup>11</sup>C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile, [<sup>11</sup>C]DASB, is suitable for imaging and quantification of transporters in rats and rhesus monkeys. In addition, the binding of [<sup>11</sup>C]DASB in brain tissue is decreased when 5HT concentrations are increased by tranylcypromine administration. The sensitivity of [<sup>11</sup>C]DASB binding, under these experimental conditions, to increased endogenous 5HT concentrations demonstrates the potential of in vivo monitoring of 5HT release in rat and monkey models.</p><p>The irreversible binding of 5-hydroxy-L-[β-<sup>11</sup>C]tryptophan, [<sup>11</sup>C]HTP, in the monkey brain was lower in the presence of NSD1015, which was used to inhibit the decarboxylase step in 5HT synthesis. [<sup>11</sup>C]HTP seems thus to have potential for tracking changes in the activity of this biosynthesis enzyme. In contrast, the accumulation of [<sup>11</sup>C]HTP was unaffected by clorgyline, which was used to inhibit metabolism of the probe in the brain. This appears to indicate that elimination of the main metabolite from the brain could be negligible and thus will not alter [<sup>11</sup>C]HTP quantification. The extent and distribution of the irreversible binding of a substrate for the first enzyme in 5HT formation, α-[<sup>11</sup>C]methyl-L-tryptophan, [<sup>11</sup>C]AMT, was different from those for [<sup>11</sup>C]HTP. This suggests that the two studied probe compounds provide estimates related to the enzyme activity of different steps in the 5HT biosynthesis pathway. </p><p>A reference tissue version of the Patlak method for the analysis of data obtained by PET was also developed. This approach takes into account irreversible binding in the reference region and appears, therefore, to yield more reliable parameter estimates than the conventional reference Patlak analysis. The method is recommended for parameter estimation of [<sup>11</sup>C]HTP data when no metabolite-corrected plasma curve is available. </p><p>Knowledge of altered 5HT synthesis and release in disease states and the consequences for effective pharmacotherapy can improve our knowledge of the aetiology of certain psychiatric and neurological diseases and enhance our ability to design more effective drugs.</p>
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Pharmacokinetic drug-drug interactions in the management of malaria, HIV and tuberculosisElsherbiny, Doaa January 2008 (has links)
<p> Malaria, Human Immunodeficiency Virus (HIV) and tuberculosis (TB) are global health problems having their worst situation in sub-Saharan Africa. Consequently, concomitant use of antimalarial, antiretroviral and antitubercular drugs may be needed, resulting in a potential risk of drug-drug interactions.</p><p>Cytochrome P-450 (CYP) enzyme induction/inhibition may lead to drug-drug interactions and can be detected by probe drugs. An analytical method was developed for the quantitation of mephenytoin, CYP2B6 and CYP2C19 probe, and its metabolites. </p><p>Induction/inhibition of principal CYP enzymes by the antimalarials; artemisinin, dihydroartemisinin, arteether, artemether and artesunate, was evaluated using the 4-hour plasma concentration ratios of probe drugs and their metabolites along with modelling the population pharmacokinetics of S-mephenytoin and its metabolites. The extent of change in enzymatic activities was different among the antimalarials, with artemisinin having strongest capacity for induction and inhibition, consequently, the strongest potential risk for drug-drug interactions. </p><p>Drug-drug interactions between the antitubercular rifampicin and the antiretrovirals nevirapine and lopinavir were assessed, in TB/HIV patients, by developing population pharmacokinetic models. Rifampicin increased nevirapine oral clearance. Simulations suggested that increasing the nevirapine dose to 300 mg twice daily when co-administered with rifampicin, would result in nevirapine concentrations above subtherapeutic levels, with minimum exposure above the recommended maximum concentration. Lopinavir is co-formulated with ritonavir in the ratio of 4:1. In children, increasing ritonavir dose four times did not completely compensate the enhancement of lopinavir oral clearance caused by rifampicin. However, the predicted lopinavir trough concentration was above the recommended minimum therapeutic concentration.</p><p>The work presented in this thesis followed an investigation line though not done for a particular drug. First the CYP enzymes involved in the interaction are identified. Afterwards, the expected drug-drug interaction is investigated where the potentially interacting drugs are concomitantly administered and an adjustment in the dose regimen is proposed that is subsequently evaluated.</p>
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Pharmacokinetic drug-drug interactions in the management of malaria, HIV and tuberculosisElsherbiny, Doaa January 2008 (has links)
Malaria, Human Immunodeficiency Virus (HIV) and tuberculosis (TB) are global health problems having their worst situation in sub-Saharan Africa. Consequently, concomitant use of antimalarial, antiretroviral and antitubercular drugs may be needed, resulting in a potential risk of drug-drug interactions. Cytochrome P-450 (CYP) enzyme induction/inhibition may lead to drug-drug interactions and can be detected by probe drugs. An analytical method was developed for the quantitation of mephenytoin, CYP2B6 and CYP2C19 probe, and its metabolites. Induction/inhibition of principal CYP enzymes by the antimalarials; artemisinin, dihydroartemisinin, arteether, artemether and artesunate, was evaluated using the 4-hour plasma concentration ratios of probe drugs and their metabolites along with modelling the population pharmacokinetics of S-mephenytoin and its metabolites. The extent of change in enzymatic activities was different among the antimalarials, with artemisinin having strongest capacity for induction and inhibition, consequently, the strongest potential risk for drug-drug interactions. Drug-drug interactions between the antitubercular rifampicin and the antiretrovirals nevirapine and lopinavir were assessed, in TB/HIV patients, by developing population pharmacokinetic models. Rifampicin increased nevirapine oral clearance. Simulations suggested that increasing the nevirapine dose to 300 mg twice daily when co-administered with rifampicin, would result in nevirapine concentrations above subtherapeutic levels, with minimum exposure above the recommended maximum concentration. Lopinavir is co-formulated with ritonavir in the ratio of 4:1. In children, increasing ritonavir dose four times did not completely compensate the enhancement of lopinavir oral clearance caused by rifampicin. However, the predicted lopinavir trough concentration was above the recommended minimum therapeutic concentration. The work presented in this thesis followed an investigation line though not done for a particular drug. First the CYP enzymes involved in the interaction are identified. Afterwards, the expected drug-drug interaction is investigated where the potentially interacting drugs are concomitantly administered and an adjustment in the dose regimen is proposed that is subsequently evaluated.
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