Optimizing visceral leishmaniasis treatment in Eastern Africa: Understanding the pharmacokinetics and pharmacodynamics in a pediatric and malnourished population

Abstract

Visceral leishmaniasis (VL) is a neglected tropical disease caused by the Leishmania parasite. There is a critical need for development of more effective and user-friendly treatment and diagnostics for this devastating and potentially fatal disease, especially in Eastern Africa, where treatment efficacy is suboptimal in this vulnerable and mainly pediatric population. To minimize the risks for either treatment failure or toxicity, VL drugs should be dosed precisely to reach the right drug exposure in the patient. To achieve this, pharmacokinetic studies are needed to describe the absorption, distribution, metabolism and elimination of VL drugs. In the first part of this thesis, the pharmacokinetics of paromomycin and miltefosine were studied, two favorable treatment options for VL. An optimized paromomycin-miltefosine combination regimen in Eastern African VL patients was developed, resulting in satisfactory cure rates and desired drug exposure levels in both pediatric and adult patients. Moreover, the impact of malnutrition and severity of disease on drug pharmacokinetics and exposure were studied and substantial and potentially clinically relevant effects of these factors were discovered. Secondly, the Leishmania parasite dynamics has been characterized in VL patients and the relationship between blood parasite load and relapse of disease, which is a long-term event that is difficult to predict. This thesis demonstrated that blood parasite load is a promising biomarker to predict relapse of disease already early after treatment. The knowledge gained in this thesis is a step forward to optimization, individualization and monitoring of VL treatment in Eastern Africa.