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<p>Enzyme induction is a process whereby a molecule enhances the expression of enzymes. If the affected enzymes are involved in the elimination of a drug, this may result in a drug interaction. Induction is therefore of major concern during drug development and in clinical practice. </p><p>The induction process depends on the half-life of the induced enzyme, the pharmacokinetics of the inducing agent, and the relationship between the inducer’s concentration and the induction stimulus. The aim of the conducted research was to investigate these key aspects of enzyme induction and the consequences that induction has for substrate elimination.</p><p>Successful investigations of the induction process presuppose the existence of appropriate methods for the estimation of the metabolic activity. Enzyme activity measurements can be conducted in tissues with low enzyme content using the analytical method presented here. </p><p>A model was developed describing the changes in the pharmacokinetics of clomethiazole and its metabolite NLA-715, that are attributable to carbamazepine induction. The consequences of the induction was explained using a mechanistic approach, acknowledging food-induced changes in the blood flow to the liver, and interpreting in vitro generated metabolic information.</p><p>The time course of the induction process was examined in two investigations. In the first of these, the pharmacokinetics of the autoinducing drug phenobarbital and its effect on several enzymes were described in rats. This was accomplished by integrating the bidirectional interaction between drug and enzymes in a mechanistic manner. In the final investigation, the time course of the increase and cessation in enzyme activity was studied in healthy volunteers treated with carbamazepine. This investigation allowed the half-lives of CYP3A and CYP1A2 to be estimated. </p><p>The key aspects of the enzyme induction process have been examined using mechanistic induction models. These novel models improve the understanding of the induction process and its consequences for substrate elimination.</p>

Enzyme induction is a process whereby a molecule enhances the expression of enzymes. If the affected enzymes are involved in the elimination of a drug, this may result in a drug interaction. Induction is therefore of major concern during drug development and in clinical practice. The induction process depends on the half-life of the induced enzyme, the pharmacokinetics of the inducing agent, and the relationship between the inducer’s concentration and the induction stimulus. The aim of the conducted research was to investigate these key aspects of enzyme induction and the consequences that induction has for substrate elimination. Successful investigations of the induction process presuppose the existence of appropriate methods for the estimation of the metabolic activity. Enzyme activity measurements can be conducted in tissues with low enzyme content using the analytical method presented here. A model was developed describing the changes in the pharmacokinetics of clomethiazole and its metabolite NLA-715, that are attributable to carbamazepine induction. The consequences of the induction was explained using a mechanistic approach, acknowledging food-induced changes in the blood flow to the liver, and interpreting in vitro generated metabolic information. The time course of the induction process was examined in two investigations. In the first of these, the pharmacokinetics of the autoinducing drug phenobarbital and its effect on several enzymes were described in rats. This was accomplished by integrating the bidirectional interaction between drug and enzymes in a mechanistic manner. In the final investigation, the time course of the increase and cessation in enzyme activity was studied in healthy volunteers treated with carbamazepine. This investigation allowed the half-lives of CYP3A and CYP1A2 to be estimated. The key aspects of the enzyme induction process have been examined using mechanistic induction models. These novel models improve the understanding of the induction process and its consequences for substrate elimination.

Choline oxidase from Arthrobacter globiformis is a flavin-dependent enzyme that catalyzes the oxidation of choline to betaine aldehyde through two sequential hydride-transfer steps. The study of this enzyme is of importance to the understanding of glycine betaine biosynthesis found in pathogenic bacterial or economic relevant crop plants as a response to temperature and salt stress in adverse environment. In this study, chemical modification of choline oxidase using two irreversible inhibitors, tetranitromethane and phenylhydrazine, was performed in order to gain insights into the active site structure of the enzyme. Choline oxidase can also be inactivated irreversibly by freezing in 20 mM sodium phosphate and 20 mM sodium pyrophosphate at pH 6 and -20 oC. The results showed that enzyme inactivation was due to a localized conformational change associated with the ionization of a group in close proximity to the flavin cofactor and led to a complete lost of catalytic activity.

Spinosyn A is a particularly interesting natural product due to its structural complexity and potent insecticidal activity. The biosynthetic pathway of spinosyn A is interesting as it has two unusual features, the SpnF-catalyzed (4+2) cycloaddition and the SpnL-catalyzed cyclization to produce the perhydro-as-indacene core. The work described in this dissertation focuses on elucidating the mechanisms of the SpnF- and SpnL-catalyzed reactions. SpnF has attracted significant interest as a possible Diels-Alderase. To explain how SpnF catalyzes the formation of cyclohexene ring, three plausible mechanisms have been proposed, the Diels-Alder reaction mechanism, the ionic rearrangement mechanism, and the biradical rearrangement mechanism. Kinetic isotope effect studies were performed using four deuterium-labeled mechanistic probes, specially the C4-D, C7-D, C11-D, and C12-D analogs. Currently, the ionic rearrangement mechanism can be excluded, based on the results using the C4-D and C7-D analogs. In addition, how SpnF accelerates the reaction was studied to assess the contribution of an entropic x preorganization compared to enthalpic transition state stabilization. To measure the relative rate enhancements due to structural perturbations, three mechanistic probes were synthesized, the linear analog, the C13-14 Unc analog, and the C2-3 Unc analog. Unfortunately, the linear analog and C13-14 Unc analog didn’t show any turnover activity under either non-enzymatic or enzymatic conditions. Thus, no conclusion could be drawn from incubation with these substrate analogs. Mechanistic studies of SpnL-catalyzed cyclization were devoted to differentiating between the Rauhut-Currier type mechanism and the Michael addition mechanism. Biochemical studies using the C13-F analog as a mechanism-based inhibitor showed the formation of a covalent adduct with SpnL, which is consistent with the Rauhut-Currier type mechanism. Additional experimental data obtained from isotope trace experiments and kinetic isotope effect studies using C12-D analog supports the Rauhut-Currier type mechanism. Biochemical studies concerning the role of SAM in SpnF and SpnL showed that SAM is required for the activity of SpnL, and were inconclusive for SpnF. SpnL mutant studies showed that Cys60 and Glu96 may be important for the catalysis of SpnL. Chemoenzymatic total synthesis of spinosyn A was completed by chemical etherification of 17-pseudoaglycone and D-forosamine. / text

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.

In recent years, use of composites is increasing in most fields of engineering such as aerospace, automotive, civil construction, marine, prosthetics, etc., because of its light weight, very high specific strength and stiffness, corrosion resistance, high thermal resistance etc. It can be seen that the specific strength of fibers are many orders more compared to metals. Thus, laminated fiber reinforced plastics have emerged to be attractive materials for many engineering applications. Though the uses of composites are enormous, there is always an element of fuzziness in the design of composites. Composite structures are required to be designed to resist high stresses. For this, one requires a reliable failure criterion. The anisotropic behaviour of composites makes it very difficult to formulate failure criteria and experimentally verify it, which require one to perform necessary bi-axial tests and plot the failure envelopes. Failure criteria are usually based on certain assumption, which are some times questionable. This is because, the failure process in composites is quite complex. The failure in a composite is normally based on initiating failure mechanisms such as fiber breaks, fiber compressive failure, matrix cracks, matrix crushing, delamination, disbonds or a combination of these. The initiating failure mechanism is the one, which is/are responsible for initiating failure in a laminated composites. Initiating failure mechanisms are generally dependant on the type of loading, geometry, material properties, condition of manufacture, boundary conditions, weather conditions etc. Since, composite materials exhibit directional properties, their applications and failure conditions should be properly examined and in addition to this, robust computational tools have to be exploited for the design of structural components for efficient utilisation of these materials. Design of structural components requires reliable failure criteria for the safe design of the components. Several failure criteria are available for the design of composite laminates. None of the available anisotropic strength criteria represents observed results sufficiently accurate to be employed confidently by itself in design. Most of the failure criteria are validated based on the available uniaxial test data, whereas, in practical situations, laminates are subjected to at least biaxial states of stresses. Since, the generation of biaxial test data are very difficult and time consuming to obtain, it is indeed a necessity to develop computational tools for modelling the biaxial behavior of the composite laminates. Understanding of the initiating failure mechanisms and the development of reliable failure criteria is an essential prerequisite for effective utilization of composite materials. Most of the failure criteria, considers the uniaxial test data with constant shear stress to develop failure envelopes, but in reality, structures are subjected to biaxial normal stresses as well as shear stresses. Hence, one can develop different failure envelopes depending upon the percentage of the shear stress content. As mentioned earlier, safe design of the composite structural components require reliable failure criterion. Currently two broad approaches, namely, (1) Damage Tolerance Based Design and (2)Failure Criteria Based Design are in use for the design of laminated structures in aerospace industry. Both approaches have some limitations. The damage tolerance based design suffers from a lack of proper definition of damage and the inability of analytical tools to handle realistic damage. The failure criteria based design, although relatively, more attractive in view of the simplicity, it forces the designer to use unverified design points in stress space, resulting in unpredictable failure conditions. Generally, failure envelopes are constructed using 4 or 5 experimental constants. In this type of approach, small experimental errors in these constants lead to large shift in the failure boundaries raising doubts about the reliability of the boundary in some segments. Further, they contain segments which have no experimental support and so can lead to either conservative or nonconservative designs. Conservative design leads to extra weight, a situation not acceptable in aerospace industry. Whereas, a nonconservative design, is obviously prohibitive, as it implies failure. Hence, both the damage tolerance based design and failure criteria based design have limitations. A new method, which combines the advantages of both the approaches is desirable. This issue is also thoroughly debated in many international conference on composites. Several pioneers in the composite industry indicated the need for further research work in the development of reliable failure criteria. Hence, this is motivated to carry out research work for the development of new failure criterion for the design of composite structures. Several experts meetings held world wide towards the assessment of existing failure theories and computer codes for the design of composite structures. One such meeting is the experts meeting held at United Kingdom in 1991.This meeting held at St. Albans(UK) on ’Failure of Polymeric Composites and Structures: Mechanisms and Criteria for the Prediction of Performance’, in 1991 by UK Science & Engineering Council and UK Institute of Mechanical Engineers. After thorough deliberations it was concluded that 1. There is no universal definition of failure of composites. 2. There is little or lack of faith in the failure criteria that are in current use and 3. There is a need to carry out World Wide Failure Exercise(WWFE) Based on the experts suggestions, Hinton and Soden initiated the WWFE in consultation with Prof.Bryan Harris (Editor, Journal of Composite Science and Tech-nology)to have a program to get comparative assessment of existing failure criteria and codes with following aims 1. Establish the current level of maturity of theories for predicting the failure response of fiber reinforced plastic(FRP)laminates. 2. Closing the knowledge gap between theoreticians and design practitioners in this field. 3. Stimulating the composites’ community into providing design engineers with more robust and accurate failure prediction methods, and the confidence to use them. The organisers invited pioneers in the composite industry for the program of WWFE. Among the pioneer in the composite industry Professor Hashin declined to participate in the program and had written a letter to the organisers saying that, My only work in this subject relates to failure criteria of unidirectional fiber composites, not to laminates. I do not believe that even the most complete information about failure of single plies is sufficient to predict the failure of a laminate, consisting of such plies. A laminate is a structure which undergoes a complex damage process (mostly of cracking) until it finally fails. The analysis of such a process is a prerequisite for failure analysis. ”While significant advances have been made in this direction we have not yet arrived at the practical goal of failure prediction”. Another important conference held in France in 1999, Composites for the next Millennium (Proceedingof Symposium in honor of S.W.Tsaion his 70th Birth Day Torus, France, July 2-3, 1999, pp.19.) also concludedon similar line to the meeting held at UK in 1991. Paul A Lagace and S. Mark Spearing, have pointed out that, by referring to the article on ’Predicting Failure in Composite Laminates: the background to the exercise’, by M.J.Hinton & P.D.Soden, Composites Science and Technology, Vol.58, No.7(1998), pp.1005. ”After Over thirty years of work ’The’ composite failure criterion is still an elusive entity”. Numerous researchers have produced dozens of approaches. Hundreds of papers, manuscripts and reports were written and presentations made to address the latest thoughts, add data to accumulated knowledge bases and continue the scholarly debate. Thus, the out come of these experts meeting, is that, there is a need to develop new failure theories and due to complexities associated with experimentation, especially getting bi-axial data, computational methods are the only viable alternative. Currently, biaxial data on composites is very limited as the biaxial testing of laminates is very difficult and standardization of biaxial data is yet to be done. All these experts comments and suggestions motivated us to carry out research work towards the development of new failure criterion called ’Failure Mechanism Based Failure Criterion’ based on initiating failure mechanisms. The objectives of the thesis are 1. Identification of the failure mechanism based failure criteria for the specific initiating failure mechanism and to assign the specific failure criteria for specific initiating failure mechanism, 2. Use of the ’failure mechanism based design’ method for composite pressurant tanks and to evaluate it, by comparing it with some of the standard ’failure criteria’ based designs from the point of view of overall weight of the pressurant tank, 3. Development of new failure criterion called ’Failure Mechanism Based Failure Criterion’ without shear stress content and the corresponding failure envelope, 4. Development of different failure envelopes with the effect of shear stress depending upon the percentage of shear stress content and 5. Design of composite laminates with the Failure Mechanism Based Failure Criterion using optimization techniques such as Genetic Algorithms(GA) and Vector Evaluated Particle Swarm Optimization(VEPSO) and the comparison of design with other failure criteria such as Tsai-Wu and Maximum Stress failure criteria. The following paragraphs describe about the achievement of these objectives. In chapter 2, a rectangular panel subjected to boundary displacements is used as an example to illustrate the concept of failure mechanism based design. Composite Laminates are generally designed using a failure criteria, based on a set of standard experimental strength values. Failure of composite laminates involves different failure mechanisms depending upon the stress state and so different failure mechanisms become dominant at different points on the failure envelope. Use of a single failure criteria, as is normally done in designing laminates, is unlikely to be satisfactory for all combination of stresses. As an alternate use of a simple failure criteria to identify the dominant failure mechanism and the design of the laminate using appropriate failure mechanism based criteria is suggested in this thesis. A complete 3-D stress analysis has been carried out using a general purpose NISA Finite Element Software. Comparison of results using standard failure criteria such as Maximum Stress, Maximum Strain, Tsai-Wu, Yamada-Sun, Maximum Fiber Strain, Grumman, O’brien, & Lagace, indicate substantial differences in predicting the first ply failure. Results for Failure Load Factors, based on the failure mechanism based approach are included. Identification of the failure mechanism at highly stressed regions and the design of the component, to withstand an artificial defect, representative this failure mechanism, provides a realistic approach to achieve necessary strength without adding unnecessary weight to the structure. It is indicated that the failure mechanism based design approach offers a reliable way of assessing critically stressed regions to eliminate the uncertainties associated with the failure criteria. In chapter 3, the failure mechanism based design approach has been applied to a composite pressurant tanks of upper stages of launch vehicles and propulsion systems of space crafts. The problem is studied using the failure mechanism based design approach, by introducing an artificial matrix crack representative of the initiating failure mechanism in the highly stressed regions and the strain energy release rate (SERR) are calculated. The total SERR value is obtained as 3330.23 J/m2, which is very high compared to the Gc(135 J/m2) value, which means the crack will grow further. The failure load fraction at which the crack has a tendency to grow is estimated to be 0.04054.Results indicates that there are significant differences in the failure load fraction for different failure criteria.Comparison with Failure Mechanism Based Criterion (FMBC) clearly indicates matrix cracks occur at loads much below the design load yet fibers are able to carrythe design load. In chapter 4, a Failure Mechanism Based Failure Criterion(FMBFC)has been proposed for the development of failure envelope for unidirectional composite plies. A representative volume element of the laminate under local loading is micromechanically modelled to predict the experimentally determined strengths and this model is then used to predict points on the failure envelope in the neighborhood of the experimental points. The NISA finite element software has been used to determine the stresses in the representative volume element. From these micro-stresses, the strength of the lamina is predicted. A correction factor is used to match the prediction of the present model with the experimentally determined strength so that, the model can be expected to provide accurate prediction of the strength in the neighborhood of the experimental points. A procedure for the construction of the failure envelope in the stress space has been outlined and the results are compared with the some of the standard and widely used failure criteria in the composite industry. Comparison of results with the Tsai-Wu failure criterion shows that there are significant differences, particularly in the third quadrant, when the ply is under bi-axial compressive loading. Comparison with maximum stress criterion indicates better correlation. The present failure mechanism based failure criterion approach opens a new possibility of constructing reliable failure envelopes for bi-axial loading applications, using the standard uniaxialtest data. In chapter 5, the new failure criterion for laminated composites developed based on initiating failure mechanism as mentioned in chapter 4 for without shear stress condition is extended to obtain the failure envelopes with the shear stress condition. The approach is based on Micromechanical analysis of composites, wherein a representative volume consists of a fiber surrounded by matrix in appropriate volume fraction and modeled using 3-D finite elements to predict the strengths.In this chapter, different failure envelopes are developed by varying shear stress say from 0% of shear strength to 100% of shear strength in steps of 25% of shear strength. Results obtained from this approach are compared with Tsai-Wu and Maximum stress failure criteria. The results show that the predicted strengths match more closely with maximum stress criterion. Hence, it can be concluded that influence of shear stress on the failure of the lamina is of little consequence as far as the prediction of strengths in laminates. In chapter 6, the failure mechanism based failure criterion, developed by the authors is used for the design optimization of the laminates and the percentage savings in total weight of the laminate is presented. The design optimization of composite laminates are performed using Genetic Algorithms. The genetic algorithm is one of the robust tools available for the optimum design of composite laminates. The genetic algorithms employ techniques originated from biology and dependon the application of Darwin’s principle of survival of the fittest. When a population of biological creatures is permitted to evolve over generations, individual characteristics that are beneficial for survival have a tendency to be passed on to future generations, since individuals carrying them get more chances to breed. In biological populations, these characteristics are stored in chromosomal strings. The mechanics of natural genetics is derived from operations that result in arranged yet randomized exchange of genetic information between the chromosomal strings of the reproducing parents and consists of reproduction, cross over, mutation, and inversion of the chromosomal strings. Here, optimization of the weight of the composite laminates for given loading and material properties is considered. The genetic algorithms have the capability of selecting choice of orientation, thickness of single ply, number of plies and stacking sequence of the layers. In this chapter, minimum weight design of composite laminates is presented using the Failure Mechanism Based(FMB), Maximum Stress and Tsai-Wu failure criteria. The objective is to demonstrate the effectiveness of the newly proposed FMB Failure Criterion(FMBFC) in composite design. The FMBFC considers different failure mechanisms such as fiber breaks, matrix cracks, fiber compressive failure, and matrix crushing which are relevant for different loadin gconditions. FMB and Maximum Stress failure criteria predicts byupto 43 percent savings in weight of the laminates compared to Tsai-Wu failure criterion in some quadrants of the failure envelope. The Tsai-Wu failure criterion over predicts the weight of the laminate by up to 86 percent in the third quadrant of the failure envelope compared to FMB and Maximum Stress failure criteria, when the laminate is subjected to biaxial compressive loading. It is found that the FMB and Maximum Stress failure criteria give comparable weight estimates. The FMBFC can be considered for use in the strength design of composite structures. In chapter 7, Particle swarm optimization is used for design optimization of composite laminates. Particle swarm optimization(PSO)is a novel meta-heuristic inspired by the flocking behaviour of birds. The application of PSO to composite design optimization problems has not yet been extensively explored. Composite laminate optimization typically consists in determining the number of layers, stacking sequence and thickness of ply that gives the desired properties. This chapter details the use of Vector Evaluated Particle Swarm Optimization(VEPSO) algorithm, a multi-objective variant of PSO for composite laminate design optimization. VEPSO is a modern coevolutionary algorithm which employs multiple swarms to handle the multiple objectives and the information migration between these swarms ensures that a global optimum solution is reached. The current problem has been formulated as a classical multi-objective optimization problem, with objectives of minimizing weight of the component for a required strength and minimizing the totalcost incurred, such that the component does not fail. In this chapter, an optimum configuration for a multi-layered unidirectional carbon/epoxy laminate is determined using VEPSO. The results are presented for various loading configurations of the composite structures. The VEPSO predicts the same minimum weight optimization and percentage savings in weight of the laminate when compared to GA for all loading conditions.There is small difference in results predicted by VEPSO and GA for some loading and stacking sequence configurations, which is mainly due to random selection of swarm particles and generation of populations re-spectively.The difference can be prevented by running the same programme repeatedly. The Thesis is concluded by highlighting the future scope of several potential applications based on the developments reported in the thesis.

<p>A central aim in drug development is to ensure that the new drug is efficacious and safe in the intended patient population.</p><p>Mathematical models describing the pharmacokinetic-pharmacodynamic (PK-PD) properties of a drug are valuable to increase the knowledge about drug effects and disease and can be used to inform decisions. The aim of this thesis was to develop mechanism-based PK-PD-disease models for important safety and efficacy biomarkers used in anti-diabetic drug development. </p><p>Population PK, PK-PD and disease models were developed, based on data from clinical studies in subjects with varying degrees of renal function, non-diabetic subjects with insulin resistance and patients with type 2 diabetes mellitus (T2DM), receiving a peroxisome proliferator-activated receptor (PPAR) α/γ agonist, tesaglitazar.</p><p>The PK model showed that a decreased renal elimination of the metabolite in renally impaired subjects leads to increased levels of metabolite undergoing interconversion and subsequent accumulation of tesaglitazar. Tesaglitazar negatively affects the glomerular filtration rate (GFR), and since renal function affects tesaglitazar exposure, a PK-PD model was developed to simultaneously describe this interrelationship. The model and data showed that all patients had decreases in GFR, which were reversible when discontinuing treatment. </p><p>The PK-PD model described the interplay between fasting plasma glucose (FPG), glycosylated haemoglobin (HbA1c) and haemoglobin in T2DM patients. It provided a mechanistically plausible description of the release and aging of red blood cells (RBC), and the glucose dependent glycosylation of RBC to HbA1c. The PK-PD model for FPG and fasting insulin, incorporating components for β-cell mass, insulin sensitivity and impact of disease and drug treatment, realistically described the complex glucose homeostasis in the heterogeneous patient population. </p><p>The mechanism-based PK, PK-PD and disease models increase the understanding about T2DM and important biomarkers, and can be used to improve decision making in the development of future anti-diabetic drugs. </p>

A central aim in drug development is to ensure that the new drug is efficacious and safe in the intended patient population. Mathematical models describing the pharmacokinetic-pharmacodynamic (PK-PD) properties of a drug are valuable to increase the knowledge about drug effects and disease and can be used to inform decisions. The aim of this thesis was to develop mechanism-based PK-PD-disease models for important safety and efficacy biomarkers used in anti-diabetic drug development. Population PK, PK-PD and disease models were developed, based on data from clinical studies in subjects with varying degrees of renal function, non-diabetic subjects with insulin resistance and patients with type 2 diabetes mellitus (T2DM), receiving a peroxisome proliferator-activated receptor (PPAR) α/γ agonist, tesaglitazar. The PK model showed that a decreased renal elimination of the metabolite in renally impaired subjects leads to increased levels of metabolite undergoing interconversion and subsequent accumulation of tesaglitazar. Tesaglitazar negatively affects the glomerular filtration rate (GFR), and since renal function affects tesaglitazar exposure, a PK-PD model was developed to simultaneously describe this interrelationship. The model and data showed that all patients had decreases in GFR, which were reversible when discontinuing treatment. The PK-PD model described the interplay between fasting plasma glucose (FPG), glycosylated haemoglobin (HbA1c) and haemoglobin in T2DM patients. It provided a mechanistically plausible description of the release and aging of red blood cells (RBC), and the glucose dependent glycosylation of RBC to HbA1c. The PK-PD model for FPG and fasting insulin, incorporating components for β-cell mass, insulin sensitivity and impact of disease and drug treatment, realistically described the complex glucose homeostasis in the heterogeneous patient population. The mechanism-based PK, PK-PD and disease models increase the understanding about T2DM and important biomarkers, and can be used to improve decision making in the development of future anti-diabetic drugs.

Type 2 diabetes is a complex chronic metabolic disorder characterized by hyperglycemia associated with a relative deficiency of insulin secretion and a reduced response of target tissues to insulin. Considerable efforts have been put into the development of models describing the glucose-insulin system. The best known is Bergman’s “minimal” model for glucose, which is estimating glucose concentrations using fixed insulin concentrations as input. However, due to the involved feedback mechanisms, simultaneous modeling of both entities would be advantageous. This is particularly relevant if the model is intended to be used as a predictive tool. The mechanism-based glucose-insulin model presented in this thesis is able to simultaneously describe glucose and insulin profiles following a wide variety of clinical provocation experiments, such as intravenous and oral glucose tolerance tests, clamp studies and sequential meal tests over 24 hours. It consists of sub-models for glucose, labeled glucose and insulin kinetics. It also incorporates control mechanisms for the regulation of glucose production, insulin secretion, and glucose uptake. Simultaneous analysis of all data by nonlinear mixed effect modeling was performed in NONMEM. Even if this model is a crude representation of a complex physiological system, its ability to represent the main processes of this system was established by identifying: 1) the difference in insulin secretion and insulin sensitivity between healthy volunteers and type 2 diabetics, 2) the action of incretin hormones after oral administration of glucose, 3) the circadian variation of insulin secretion and 4) the correct mechanism of action of a glucokinase activator, a new oral antidiabetic compound acting on both the pancreas and the liver. These promising results represent a proof of concept of a mechanistic drug-disease model that could play an important role in the clinical development of anti-diabetic drugs.