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

Gert-Jan Wijnant,Charles Mowbray,Katrien Van Bocxlaer,Vanessa Yardley,Mo Alavijeh,Stéphanie Braillard,Simon L Croft,Raul De La Flor

doi:10.1128/aac.00829-19

Abstract

The nitroimidazole DNDI-0690 is a clinical drug candidate for visceral leishmaniasis (VL) that also shows potent in vitro and in vivo 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 Leishmania 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 [fAUC0-6 h, skin tissue/fAUC0-6 h, blood] is greater than 80%). Based on in vivo bioluminescence imaging, two doses of 50 mg/kg DNDI-0690 were sufficient to reduce the Leishmania mexicana parasite load by 100-fold, while 6 such doses were needed to achieve similar killing of L. major; this was confirmed by quantitative PCR. The combination of rapid accumulation and potent activity in the Leishmania-infected dermis indicates the potential of DNDI-0690 as a novel oral treatment for CL.

Highlights

The nitroimidazole DNDI-0690 is a clinical drug candidate for visceral leishmaniasis (VL) that shows potent in vitro and in vivo activity against cutaneous leishmaniasis (CL)
The antileishmanial activity of the nitroimidazooxazine DNDI-0690 (Fig. 1) was first discovered in 2015; it is a structural analogue of DNDI-VL-2098 [14], a promising oral drug candidate for VL [15, 16] that was discontinued from further development due to toxicity issues identified during nonclinical clinical trial application-enabling studies [6]
Six hours after application of a solution of DNDI-0690 saturated in propylene glycol-ethanol (PG-EtOH; 0.063% [wt/vol]), about 99.5% of the drug remained on the skin surface

Summary

Introduction

The nitroimidazole DNDI-0690 is a clinical drug candidate for visceral leishmaniasis (VL) that shows potent in vitro and in vivo 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 Leishmania pathogen. DNDi defines the optimal target product profile (TPP) of a new chemical entity for CL as follows: (i) activity against all species of Leishmania causing CL (Ͼ15), (ii) a minimum 95% clinical efficacy and minimal scarring after accelerated healing of the skin lesions, (iii) use as an oral or topical formulation for a maximum of 7 or 14 days, respectively, (iv) well tolerated and safe in pregnancy, and (v) a cost under $5 per course [8]. With the clinical evaluation of DNDI-0690 for VL under way, important questions about the suitability, including appropriate pharmacokinetics (PK) and pharmacodyaac.asm.org 2

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