Pharmacokinetics and Pharmacodynamics of the Nitroimidazole DNDI-0690 in Mouse Models of Cutaneous Leishmaniasis

Abstract

The nitroimidazole DNDI-0690 is a clinical drug candidate for visceral leishmaniasis (VL) that also shows potent <i>in vitro</i> and <i>in vivo</i> activity against cutaneous leishmaniasis (CL). To support further development of this compound into a patient-friendly oral or topical formulation for the treatment of CL, we investigated the free drug exposure at the dermal site of infection and subsequent elimination of the causative <i>Leishmania</i> pathogen. This study evaluates the pharmacokinetics (PK) and pharmacodynamics (PD) of DNDI-0690 in mouse models of CL. Skin microdialysis and Franz diffusion cell permeation studies revealed that DNDI-0690 permeated poorly (<1%) into the skin lesion upon topical drug application (0.063% [wt/vol], 30 μl). In contrast, a single oral dose of 50 mg/kg of body weight resulted in the rapid and nearly complete distribution of protein-unbound DNDI-0690 from the plasma into the infected dermis (ratio of the area under the curve [0 to 6 h] of the free DNDI-0690 concentration in skin tissue to blood [<i>f</i>AUC_{0-6 h, skin tissue}/<i>f</i>AUC_{0-6 h, blood}] is greater than 80%). Based on <i>in vivo</i> bioluminescence imaging, two doses of 50 mg/kg DNDI-0690 were sufficient to reduce the <i>Leishmania mexicana</i> parasite load by 100-fold, while 6 such doses were needed to achieve similar killing of <i>L. major</i>; this was confirmed by quantitative PCR. The combination of rapid accumulation and potent activity in the <i>Leishmania</i>-infected dermis indicates the potential of DNDI-0690 as a novel oral treatment for CL.