Author: Rasmus Hansen Henninger, MS, and Thomas P. C. Dorlo, PhD on July 21, 2026 
Figure. Model-predicted L. major parasite load reduction in humans following 14 days qd DNDI-6148 treatment at doses of 4.0 to 6.0 mg/kg (n = 10,000 per dose scenario), based on the final human PK/PD model. The bold line represents the median; the shaded area indicates the 95% confidence interval. Abbreviation: qd, once daily.
For the neglected tropical skin infection cutaneous leishmaniasis, there is only one approved oral treatment, which is limited by safety and efficacy concerns, underscoring the urgent need for better oral therapies. Drugs for Neglected Diseases initiative (DNDi) has identified DNDI-6148 as a preclinical oral candidate for cutaneous leishmaniasis, yet little is known about its ability to reach the skin target site of infection. In the current study, we developed the first translational modelling framework for cutaneous leishmaniasis that incorporates both skin target-site pharmacokinetics and pharmacodynamics, enabling prediction and exploration of human drug exposure and associated parasite clearance, guiding Phase II dose selection and clinical trial design.
For this purpose, we characterised the plasma and skin tissue pharmacokinetics of DNDI-6148 and evaluated its target-site exposure-response relationships in a murine Leishmania major infection model using a nonlinear mixed-effects modelling approach. The established exposure-response relationship was integrated with scaled human pharmacokinetics, and a probability of target attainment analysis in human suggested that daily oral doses of 4.0 or 6.0 mg/kg for 14 days would achieve a high probability of therapeutic success for cutaneous leishmaniasis, aiming for parasite reductions of 95% and 99%, respectively (see Figure). These findings highlight how model-informed translation can support dose selection and development of new oral treatments for cutaneous leishmaniasis.
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