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- Cullberg, Marie, 1958-
(author)
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Direct Thrombin Inhibitors in Treatment and Prevention of Venous Thromboembolism: Dose – Concentration – Response Relationships
- 2006
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Doctoral thesis (other academic/artistic)abstract
- For prevention and treatment of thrombotic diseases with an anticoagulant drug it is important that an adequate dose is given to avoid occurrence or recurrence of thrombosis, without increasing the risk of bleeding and other adverse events to unacceptable levels. The aim of this thesis was to develop mathematical models that describe the dose-concentration (pharmacokinetic) and concentration-response (pharmacodynamic) relationships of direct thrombin inhibitors, in order to estimate optimal dosages for treatment and long-term secondary prevention of venous thromboembolism (VTE).Population pharmacokinetic-pharmacodynamic models were developed, based on data from clinical investigations in healthy volunteers and patients receiving intravenous inogatran, subcutaneous melagatran and/or its oral prodrug ximelagatran. The benefit-risk profiles of different ximelagatran dosages were estimated using clinical utility functions. These functions were based on the probabilities and fatal consequences of thrombosis, bleeding and elevation of the hepatic enzyme alanine aminotransferase (ALAT).The studies demonstrate that the pharmacokinetics of melagatran and ximelagatran were predictable and well correlated to renal function. The coagulation marker, activated partial thromboplastin time (APTT), increased non-linearly with increasing thrombin inhibitor plasma concentration. Overall, the systemic melagatran exposure (AUC) and APTT were similarly predictive of thrombosis and bleedings. The identified relationship between the risk of ALAT-elevation and melagatran AUC suggests that the incidence approaches a maximum at high exposures. The estimated clinical utility was favourable compared to placebo in the overall study population and in special subgroups of patients following fixed dosing of ximelagatran for long-term secondary prevention of VTE. Individualized dosing was predicted to add limited clinical benefit in this indication.The models developed can be used to support the studied dosage and for selection of alternative dosing strategies that may improve the clinical outcome of ximelagatran treatment. In addition, the models may be extrapolated to aid the dose selection in clinical trials with other direct thrombin inhibitors.
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| 2. |
- Kjellsson, Maria C., 1975-
(author)
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Methodological Studies on Models and Methods for Mixed-Effects Categorical Data Analysis
- 2008
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Doctoral thesis (other academic/artistic)abstract
- Effects of drugs are in clinical trials often measured on categorical scales. These measurements are increasingly being analyzed using mixed-effects logistic regression. However, the experience with such analyzes is limited and only a few models are used. The aim of this thesis was to investigate the performance and improve the use of models and methods for mixed-effects categorical data analysis. The Laplacian method was shown to produce biased parameter estimates if (i) the data variability is large or (ii) the distribution of the responses is skewed. Two solutions are suggested; the Gaussian quadrature method and the back-step method. Two assumptions made with the proportional odds model have also been investigated. The assumption with proportional odds for all categories was shown to be unsuitable for analysis of data arising from a ranking scale of effects with several underlying causes. An alternative model, the differential odds model, was developed and shown to be an improvement, in regard to statistical significance as well as predictive performance, over the proportional odds model for such data. The appropriateness of the likelihood ratio test was investigated for an analysis where dependence between observations is ignored, i.e. performing the analysis using the proportional odds model. The type I error was found to be affected; thus assessing the actual critical value is prudent in order to verify the statistical significance level. An alternative approach is to use a Markov model, in which dependence between observations is incorporated. In the case of polychotomous data such model may involve considerable complexity and thus, a strategy for the reduction of the time-consuming model building with the Markov model and sleep data is presented. This thesis will hopefully contribute to a more confident use of models for categorical data analysis within the area of pharmacokinetic and pharmacodynamic modelling in the future.
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| 3. |
- Silber, Hanna, 1977-
(author)
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Integrated Modeling of Glucose and Insulin Regulation Following Provocation Experiments
- 2009
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Doctoral thesis (other academic/artistic)abstract
- Blood glucose is controlled by a complex system of insulin and other hormones to assure a constant supply of glucose to the tissues. Type 2 diabetes is a metabolic disorder which is characterized by progressively worsening glycemic control due to a relative deficiency of insulin secretion and a decreased response to insulin. Numerous mathematical models have been developed with the aim of describing glucose and insulin regulation. A drawback with most previously presented models is that they use an open-loop approach which simplifies the model development but at the same time limits the possible use for predictive purposes. The integrated glucose-insulin model presented in this thesis is a semi-mechanistic model which describes glucose and insulin simultaneously. The model has been used to analyze both intravenous and oral provocations and has been shown to describe and predict healthy and diabetic individuals well. Important differences between healthy and diabetic individuals were identified in insulin secretion and sensitivity. The model was used for design optimization of the intravenous glucose tolerance test and it was shown that the design could be improved and simplified by reduction of the number of samples and by change of glucose and insulin dose. Two methodological aspects which were of importance for model development were evaluated. These were (i) comparison of methods for incorporation of baseline data, and (ii) evaluation of the effects of model misspecification on hypothesis testing for covariate inclusion. Baseline information should be included in the model using either of three presented methods and normalization or subtraction of baseline should be avoided. The likelihood ratio test performed well in most cases except when serial correlation was present. In conclusion, a new model for glucose and insulin regulation has been proposed which is expected to play an important role in clinical development of anti-diabetic drugs.
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| 4. |
- Zingmark, Per-Henrik, 1972-
(author)
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Models for Ordered Categorical Pharmacodynamic Data
- 2005
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Doctoral thesis (other academic/artistic)abstract
- 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. 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. 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.
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