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 Emax relationship, driven by free skin concentrations (fEC50: 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.
Henninger et al. (Wed,) studied this question.