title: THE PHARMACOKINETICS AND PHARMACODYNAMICS OF ANTIFUNGAL AGENTS FOR HIV-ASSOCIATED INVASIVE FUNGAL INFECTIONS
Creators: name: Stott, Katharine
Publisher: name: University of Liverpool Repository
Year: 2021

description: Fungal infections cause an estimated 13 million life-threatening infections and 1.6 million deaths annually. The burden of invasive fungal infections (IFIs) reflects immunocompromise resulting from the rise in HIV/AIDS and iatrogenic immunosuppressive therapy. Cryptococcal meningoencephalitis and disseminated talaromycosis are archetypal conditions to illustrate the unmet medical need of IFIs. The optimum treatment regimens for cryptococcal meningoencephalitis and disseminated talaromycosis are unclear. As an alternative to serial clinical trials, PK-PD approaches offer enhanced efficiency, reduced cost and reduced risk to patients. Asides from PK parameters, additional factors that may influence treatment response include the host response to infection. This thesis begins with an overview of the historical context of antifungal PK-PD, the wide-ranging factors that influence it and methods of measuring and modelling it. Following this, a population PK model of fluconazole in cryptococcal meningoencephalitis quantifies the variability of fluconazole penetration into cerebrospinal fluid (CSF) in 43 patients. Simulations predict a low probability of PK-PD target attainment at widely used dosages of fluconazole. A meta-analysis of studies reporting clinical outcomes from fluconazole monotherapy demonstrates only minor improvements in PD and clinical outcomes with escalating dosage. A second PK model describes the population PK of amphotericin B deoxycholate (DAmB) in 42 patients treated for cryptococcal meningoencephalitis. Inter-patient variability in DAmB PK is modest and unlikely to account for variability in clinical outcome. A meta-analysis of trials reporting clinical outcomes from DAmB monotherapy suggests that DAmB dosage explains most heterogeneity in CSF sterility, but not mortality outcomes. A third population model assesses the PK of liposomal amphotericin B (LAmB) administered as a single high dose to 32 patients with cryptococcal meningoencephalitis within an ongoing clinical trial. A bridging study is performed from murine data to predict PD outcome in humans following high dose LAmB regimens, using the posterior PK parameters derived from the population PK model. This analysis supports the dose of LAmB being used in the trial. Using data from 76 clinical trial patients, a population PK-PD model of itraconazole in disseminated talaromycosis is constructed. While the model describes considerable variability in the PK of both itraconazole and its active metabolite, hydroxyitraconazole, a relationship between PK and PD cannot be demonstrated. This study suggests that the trial failed to demonstrate the non-inferiority of itraconazole versus DAmB due to a PK failure, the overwhelming majority of patients failing to mount adequate itraconazole exposure. Finally, an immunophenotyping study is presented, describing networks of immune biomarkers in the CSF of patients with cryptococcal meningoencephalitis. Phagosomal function in whole blood is measured. Data are analysed from serial samples taken during the first 14 days of treatment. A proinflammatory immune signature is associated with increased phagosomal activity in monocyte populations and may contribute to favourable PD and clinical outcomes in cryptococcal meningoencephalitis. In conclusion, pharmacometric analysis has been a neglected area of research, particularly in mycology. This work demonstrates that PK-PD tools can de-risk efforts to optimise antifungal treatment regimens, enhance the efficiency of those efforts and contribute to the preservation of the precious available antifungal armamentarium.