Warfarin is one of the most widely used anticoagulants. Therapy is complicated by warfarin’s narrow therapeutic range and pronounced variability in individual dose requirements. Although warfarin therapy is uncommon in children, it is crucial for children with certain congenital or acquired heart diseases. Treatment in children is especially difficult due to the lack of i) a decision support tool for efficient and consistent dose adjustments, and ii) a flexible warfarin formulation for accurate and reproducible dosing. The overall aim of this thesis was to develop a PKPD-based pharmacometric model for warfarin that describes the dose-response relationship over time, and to identify important predictors that influence individual dose requirements both in adults and children. Special emphasis was placed on investigating the contribution of genetic factors to the observed variability. A clinically useful pharmacometric model for warfarin has been developed using NONMEM. The model has been successfully reformulated into a KPD-model that describes the relationship between warfarin dose and INR response, and that is applicable to both adults and children. From a clinical perspective, this is a very important change since it allows the use of information on dose and INR that is available routinely. The model incorporates both patient and clinical characteristics, such as age, weight, CYP2C9 and VKORC1 genotype, and baseline and target INR, for the prediction of an individualised starting dose. It also enables the use of information from previous doses and INR observations to further individualise the dose a posteriori using a Bayesian forecasting method. The NONMEM model has been transferred to a user-friendly, platform independent tool to aid use in clinical practice. The tool can be used for a priori and a posteriori individualisation of warfarin therapy in both adults and children. The tool should ensure consistent dose adjustment practices, and provide more efficient individualisation of warfarin dosing in all patients, irrespective of age, body weight, CYP2C9 or VKORC1 genotype, baseline or target INR. The expected outcome is improved warfarin therapy compared with empirical dosing, with patients achieving a therapeutic and stable INR faster and avoiding high INRs that increase the risk of bleeding.

Abstract The global aims of this thesis were: to evaluate if an individualised dose strategy for enoxaparin, based on lean body weight and renal function, resulted in a reduction in the prevalence of bleeding and bruising events when compared to conventional dosing; to further understand the dose-exposure-response relationship for enoxaparin using population pharmacokinetic-pharmacodynamic (PKPD) modelling. This thesis comprises seven chapters: an introduction to the current knowledge and literature pertaining to low-molecular-weight heparins (LMWHs), in particular enoxaparin; five research chapters; and a discussion. Each of the five research chapters consists of a manuscript that has been published in, accepted or submitted for peer review in a scientific journal. Preceding each chapter is a synopsis of the important features of the publication. Supplementary information that supports the findings of the publication, but could not be included in the publication, is provided at the end of the chapter. Appendices relevant to each chapter are located at the end of the thesis. Chapter one is the introduction to this thesis. It commences with an overview of the LMWHs, their mechanism of action, customary uses, licensed doses and adverse effects. There is a brief introduction to renal function and body composition; physiological factors that influence the disposition of LMWHs. As much of this thesis is centred on defining the dose-exposure-response relationship for enoxaparin, there is a critique of the existing literature relevant to each segment of this relationship, namely: dose-exposure, exposure-response and dose-response. To conclude this chapter there is a review of pharmacostatistical models and population modelling, followed by an appraisal of population PK and PKPD models that have previously been developed for enoxaparin, including the two key publications that are critical to this thesis. These two papers were the first to fully describe the dose-exposure relationship for enoxaparin in subjects with renal impairment and obesity. It is from these studies that the individualised dosing strategy, explored throughout this thesis, was developed. The specific aims of the five research chapters are then stated. Chapter two describes a confirmatory, randomised controlled trial (RCT) to compare an individualised dose of enoxaparin to conventional, label based dosing. The RCT was conducted at a major tertiary teaching hospital over an 18 month period. The primary endpoint was the prevalence of overt bleeding events and the secondary endpoint a combination of bleeding or major bruising events. A time-to-bleeding event analysis (Kaplan-Meier) was used and markers of effectiveness such as mortality and readmission were assessed out to 30 days post recruitment. Bleeding and bruising data, along with anti-Xa (aXa)-concentrations were collected for use in additional research described in chapters four and five. Chapter three details the evolution, progression and contemporary knowledge of drug dosing based on body composition and focuses on dosing in obese subjects with cardiovascular disease. The concept of dose-individualisation is explored in this chapter with reference to the methods used to normalise drug exposure across the spectrum of body compositions. Subsequently, there is a review of body size descriptors, such as lean body weight, that are used to scale dosing in the obese. Enoxaparin is used as a motivating example, with reference to data presented in Chapter two of this thesis. There is also a discussion about the type of research designs that are required to maximise information about PK parameters. This chapter was published within a book chapter which was intended for clinical practitioners in the discipline of cardiology. Chapter four is focused on the development and evaluation of population PK and PKPD models to describe the time-course of effects for enoxaparin. A population PK model linked to a proportional-odds model was used to describe the severity of an adverse event as a function of exposure and demographic variables. The final model was used to explore the likely occurrence of bleeding and bruising events in patients with obesity and / or renal impairment dosed using either the individualised or conventional dose strategies from Chapter two. Chapter five describes a study that was undertaken to evaluate the ability of the individualised dosing strategy to achieve and maintain aXa-concentrations within the therapeutic range (500 to 1000 IU L-1), by comparison to conventional dosing. As the confirmatory study focused on the prevalence of adverse events there was no assessment of the therapeutic capability of the dose strategies however, as aXa-concentrations were collected using a sparse design during the confirmatory study, the two dose strategies could not be compared using observed data. Therefore, the population PK model developed in Chapter four was used to predict individual subject concentration-time profiles to 120 hours of enoxaparin therapy. The time spent in the therapeutic, supra-therapeutic and sub-therapeutic ranges was computed for each subject and the dosing strategies statistically compared. This study also allowed the evaluation of the results from Chapter two from a dose-exposure perspective. Chapter six of this thesis describes a survey. The aim of this survey was to gain an understanding of how dosing strategies of enoxaparin vary in four countries, investigate if clinicians are prescribing according to the Product label, and determine the methods used to dose-individualise enoxaparin. In doing so, individual hospitals in the international community will be able to compare, critique or benchmark their own strategies to peer hospitals, as well as the current literature. The publication arising from this survey would assist in the dissemination of knowledge gained from the earlier chapters of this thesis. Chapter seven is the final discussion and conclusions of the thesis along with prospects for future research.