Population pharmacokinetics of DNDI-6148 in healthy adults.

Leishmaniasis (both visceral and cutaneous) and Chagas disease (CD) are among the most neglected tropical diseases, with limited treatment options and an urgent need for safer, more effective therapies. DNDI-6148, a benzoxaborole with anti-leishmanial and antichagasic activity, is currently under clinical development. A first-in-human (FIH), Phase 1 study (ISRCTN54981564) has recently assessed the safety, tolerability, and pharmacokinetics of DNDI-6148, demonstrating a good safety profile and, based on non-compartmental analysis, non-linear pharmacokinetics. To support dose selection for future clinical trials, we conducted a population pharmacokinetic analysis using data from the FIH study. The analysis included data from 48 healthy male participants who received a single oral dose of DNDI-6148 (10-380 mg) across eight dosing cohorts. Plasma concentrations were quantified by liquid chromatography-tandem mass spectrometry, and concentration-time data were pooled and analyzed using nonlinear mixed-effects modeling. DNDI-6148 pharmacokinetics were non-linear and best described by a one-compartment disposition model. Higher doses were associated with decreased relative bioavailability and clearance, resulting in less than dose-proportional increases in peak plasma concentrations. The median elimination half-life increased with dose, ranging from 12.6 to 33.7 hours. In summary, the population pharmacokinetic model adequately described DNDI-6148 pharmacokinetics in healthy participants. It provides a valuable tool to guide dose selection for future clinical trials in patients with leishmaniasis and Chagas disease.