Work

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

Year: 2026

Type: article

Abstract: ABSTRACT Cutaneous leishmaniasis is a neglected tropical disease with only one oral treatment option. DNDI‐6148 is an orally bioavailable compound with potent antiparasitic activity in preclinical studies. Establishing skin target‐site pharmacokinetic/pharmacodynamic (PK/PD) relationships is essential to enable its clinical development. The objective was to characterize the target‐site PK and PD of DNDI‐6148 in a murine L. major model and to predict a human efficacious dose. A nonlinear mixed‐effects PK/PD model was developed using data from L. major ‐infected BALB/c mice orally administered DNDI‐6148 (6.25–50 mg/kg, bid). The murine PD components and skin distribution characteristics were used jointly with allometrically scaled human PK parameters to predict a clinically efficacious dose. DNDI‐6148 PK in mice was described by a one‐compartment model with dose‐dependent bioavailability, saturable clearance, and a skin‐to‐plasma ratio of 0.56 [95% CI, 0.49–0.68] for both infected and non‐infected skin. Parasite clearance at the infection site followed a sigmoidal E max relationship, driven by free skin concentrations ( fEC5 0 : 165 μg/L [95% CI, 125–236]). Human PK parameters for clearance, volume of distribution, and absorption rate were predicted to 3.44 L/h, 79.5 L and 0.360 h −1 , respectively. 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. This translational PK/PD modeling framework based on a murine infection model of cutaneous leishmaniasis effectively informs human dose selection by accounting for both PK and PD at the skin target site.

Source: Clinical and Translational Science

DOI: 10.1111/cts.70535