Advancing Drug Therapy in Poverty-Related Diseases

Abstract

Poverty-related infectious diseases, such as malaria and neglected tropical diseases (NTDs), disproportionately affect underserved populations. Patients are highly heterogeneous, including many vulnerable individuals with distinct physiological and pathological characteristics. Current treatment regimens frequently rely on empirical extrapolation across diseases or standardized dosing, overlooking variability in pharmacokinetics (PK) and pharmacodynamics (PD). This thesis applies pharmacometric modeling to improve treatments for leishmaniasis, malaria, and mycetoma. Post-kala-azar dermal leishmaniasis (PKDL), a complication of visceral leishmaniasis (VL), sustains transmission and hinders elimination. Recent clinical trials evaluated 21-42 day regimens combining miltefosine with liposomal amphotericin B (LAmB) or paromomycin. Outcomes varied geographically: cure rates exceeded 80% for papular lesions in Eastern Africa but were only around 30% for macular lesions in South Asia. Target-site PK studies showed miltefosine reached the highest skin-to-plasma ratio, and despite variability, all drugs achieved in vitro susceptibility thresholds. Yet differences in baseline parasite load and lesion size strongly influenced outcomes. Systemic PK analyses demonstrated disease-specific differences. Paromomycin clearance decreased over time due to saturation in renal reabsorption, while miltefosine showed higher oral bioavailability in PKDL than VL. LAmB demonstrated saturable macrophage uptake linked to parasite burden, suggesting dosing could be reduced in South Asia while retaining efficacy. A combined drug-parasite-lesion model captured regional PK and PD differences. In Eastern Africa, parasite reduction aligned with papular lesion healing, making parasite load and lesion score reliable markers. In South Asia, macular lesions healed slowly and independently of parasite reduction, indicating the need for better assessment methods. Modeling suggested that Eastern African regimens could be shortened to 14 days, while 21 days remained optimal in South Asia. Malaria remains a major global health burden, and pyronaridine-artesunate is a recently WHO-recommended treatment for uncomplicated malaria. Pyronaridine accumulates in red blood cells and lysosomes. Population PK analyses in pregnant women with and without HIV showed unexpectedly higher exposure during pregnancy due to increased bioavailability, although variability was substantial. Malaria-associated anemia increased volume of distribution in whole blood, lowering exposure after later doses. A physiologically based PK model incorporating lysosomal sequestration and malaria-specific factors described pyronaridine disposition in both healthy and infected individuals. Higher baseline parasitemia raised early exposure, but subsequent declines in hemoglobin reduced levels, demonstrating the complex interplay between infection, host physiology, and drug distribution. Mycetoma, one of the most neglected tropical skin diseases, is caused by bacteria or fungi and often leads to severe morbidity. The fungal form, eumycetoma, is usually treated with surgery plus year-long itraconazole, which has limited efficacy and availability. The first randomized trial in Sudan tested fosravuconazole, a prodrug of ravuconazole. PK-PD analyses showed saturable kinetics but no clear exposure-response relationship. A 200 mg weekly dose was identified as preferable to 300 mg, offering a more practical and cost-effective option. This thesis demonstrates the value of pharmacometric modeling in optimizing treatments for PKDL, malaria, and mycetoma. By incorporating regional differences, pathophysiological variability, and biomarkers such as parasite load, these approaches support more effective and personalized therapies.