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Abstract
Tacrolimus is the key immunosuppressant used in most solid-organ transplant recipients, including heart transplants, to prevent graft rejection. However, tacrolimus dosing strategies are complicated by the narrow therapeutic window and considerable pharmacokinetic variability. Individualising lifelong tacrolimus therapy to avoid graft rejection and minimise adverse effects is essential for heart transplant recipients. This thesis aimed to investigate the individualisation of tacrolimus therapy in adult heart transplant recipients using the pharmacokinetic modelling approach.
In Chapter 1, I present an overview of tacrolimus clinical pharmacology, including clinical factors influencing tacrolimus pharmacokinetics (e.g., concomitant azole antifungal therapy). In Chapter 2, I explore tacrolimus dosing and monitoring practices in heart transplant recipients (n=87) at St. Vincent’s Hospital Sydney, a major heart transplant centre in Australia. Additionally, I assess the ability of a Bayesian dosing software, approved by the Therapeutic Goods Administration to predict tacrolimus concentrations in heart transplant recipients. Tacrolimus dosing and monitoring practices were discordant with the hospital guidelines. The population pharmacokinetic model integrated within the software was suitable in guiding tacrolimus dosing only after 11 days of therapy. This finding necessitated the identification of other model(s) that might be more suitable for use in heart transplant recipients, particularly for the immediate post-transplantation phase.
In Chapter 3, I conduct a systematic review summarising published population pharmacokinetic models of tacrolimus (n=69) developed from various organ transplant recipient populations. In Chapter 4, I select relevant tacrolimus models (n=17) from the systematic review and evaluated their predictive performance in heart transplant recipients (n=85). The evaluated models displayed poor predictive performances. This finding complements the work from Chapters 2 and 3 highlighting a tacrolimus model for heart transplant recipients is required.
In Chapter 5, I successfully develop a tacrolimus population pharmacokinetic model for heart transplant recipients. The model incorporated the effects of concomitant azole antifungal use, haematocrit, and body weight on tacrolimus pharmacokinetics. Model evaluation in an independent heart transplant recipient cohort displayed good model performance. The model can be implemented in clinical practice to individualise tacrolimus dosing in heart transplant recipients. In Chapter 6, I discuss the clinical implication of this work and recommendations for future research.
