Translational Pharmacokinetic-Pharmacodynamic Modeling and Efficacious Human Dose Prediction of DNDI-6148 for the Treatment of Cutaneous Leishmaniasis

Henninger RH, Schouten WM, Arana B, Gillon J-Y, Mowbray CE, Müller Kratz J, Van Bocxlaer K, Dorlo TPC Clinical and Translational Science 2026,19(4):e70535 doi: 10.1111/cts.70535

Summary: There is only one oral treatment for cutaneous leishmaniasis. DNDI-6148 is an orally bioavailable compound with potent antiparasitic activity in preclinical studies. To enable clinical development, the authors of this manuscript aimed to characterize the target-site pharmacokinetics and pharmacodynamics of DNDI-6148 in a murine Leishmania major model and to predict a human efficacious dose. A nonlinear mixed-effects pharmacokinetics/pharmacodynamics model was developed using data from L. major-infected mice orally administered DNDI-6148. The murine pharmacodynamics components and skin distribution characteristics were used jointly with allometrically scaled human pharmacokinetics parameters to predict a clinically efficacious dose. DNDI-6148 doses of 4.0 and 6.0 mg/kg once daily for 14 days were predicted to achieve 95% and 99% parasite reduction from baseline, respectively, in >90% of simulated patients.

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