Safety, tolerability and pharmacokinetics of DNDI-6148, a novel agent for leishmaniasis: A randomized, controlled, single ascending dose study in healthy participants

Abstract

Aim: The benzoxaborole derivative DNDI-6148 is an antiparasitic agent with activity against multiple Leishmania protozoan species, including L. infantum and L. donovani, which cause visceral leishmaniasis. We investigated the safety, tolerability and pharmacokinetics of single oral doses of DNDI-6148 in a randomized, parallel-group, placebo-controlled, first-in-human study in 64 healthy participants. Methods: Eight cohorts of eight participants each were enrolled. DNDI-6148, formulated as a suspension in ORA-Sweet® was administered orally as single 10–380 mg doses. Pharmacokinetics (PK) and safety were assessed for four (cohorts receiving 10–80 mg DNDI-6148) or six (cohorts receiving 160–380 mg DNDI-6148) days after dosing. Results: Sixteen adverse events (AEs) were experienced by 13 participants (20.3%), all mild or moderate in severity and resolved by the end of the study. No AE led to any participant withdrawal, and no fatal or serious AEs were reported. DNDI-6148 was relatively slowly absorbed (t<inf>max</inf> ranging between 3 and 12 h) under fasting conditions, with increase in plasma concentrations modestly sub-proportional to dose. The mean half-life was between 12.80 and 25.42 h. The fraction of the dose excreted by the kidneys as unchanged DNDI-6148 was below 0.2%. Trace amounts of three metabolites (formed by oxidation, deboronation, dehydrogenation of DNDI-6148) were detected in plasma. Conclusion: After a single administration of up to 380 mg by oral route, DNDI-6148 had an acceptable safety and tolerability profile and a favourable PK profile. These data support further clinical development.