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…
How strong is the evidence?
Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design.
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