Bidirectional Interaction Between Liposomal Amphotericin B Pharmacokinetics and Parasite Dynamics in Patients With Post-Kala-Azar Dermal Leishmaniasis: Potential Implications for Optimal Dosing.

Abstract

Post-kala-azar dermal leishmaniasis (PKDL) involves a high macrophage burden in which the Leishmania parasites reside. Liposomal amphotericin B (LAmB) plays a key role in the treatment of PKDL. The mononuclear phagocyte system (MPS) is crucial in the distribution of liposomal drugs as well as the leishmaniasis pathophysiology. This study focused on characterizing the interaction between LAmB pharmacokinetics, the MPS, and parasite dynamics for optimal dosing of LAmB in PKDL. Clinical trial data from the Indian subcontinent, involving short-course LAmB administered alone or with miltefosine, were analyzed using nonlinear mixed-effects modeling. The pharmacokinetics of LAmB were best described by a two-compartment model with a saturable LAmB uptake by the MPS. The maximum MPS uptake capacity was modeled with a baseline component and an additional disease-related component relative to the parasite burden. As treatment progressed, MPS capacity decreased with declining parasite load, resulting in a median 54% increase in the systemic LAmB exposure (AUC_0-24h) by the end of treatment. Simulations suggested that a similar parasite clearance could be achieved with a 50% lower total LAmB dose, supporting the potential efficacy of reduced dosing regimens. Combining LAmB and miltefosine further accelerated parasite clearance compared to LAmB alone. This study highlights the importance of understanding the bidirectional interactions between LAmB pharmacokinetics and parasite infection for interpreting systemic exposure and optimizing treatment approaches. If confirmed in clinical trials, reduced LAmB dosing strategies could enable more rational and cost-effective management of PKDL and other dermal leishmaniases.