Background:
Use of long-acting injectables (LAIs) has the potential to simplify tuberculosis (TB) preventive therapy (TPT) addressing issues such as pill burden and adherence. Bedaquiline (BDQ) is a key drug in new short-course regimens for treatment of rifampin-resistant TB and could provide a short-course ‘pan’-TPT option for drug-susceptible and rifampin-resistant infections. BDQ and other diarylquinolines (DARQ) have physicochemical and pharmacokinetic (PK) properties amenable to LAI formulation. The aim of this work was to preclinically characterize a new more potent DARQ as a single phase spray dried nanosuspension LAI formulations for use in TPT.
Methods:
Single intramuscular dose PK profiles for 3 DARQ LAI formulations (formulations A-C) were characterized in mice. Based on mouse PK, formulation B was tested for bactericidal activity in a validated BALB/c mouse model of TPT at single intramuscular (IM) doses of 62.5, 125 and 250 mg/kg, with the goal of maintaining a ≥36 ng/mL plasma target for 4-8 weeks. Formulations A and C were tested only at 125 mg/kg. Negative controls were untreated. Positive controls received daily (5 days/week) oral isoniazid-rifapentine (1HP), oral BDQ or oral DARQ for 4 weeks. Lung bacterial colony-forming units (CFU) counts and plasma DARQ exposures were measured 4-12 weeks after the start of treatment. Group mean CFU counts were analyzed using 1-way ANOVA and plasma exposure with non-compartmental PK analysis.
Results:
All DARQ LAI regimens had bactericidal activity over the first 4 weeks of treatment that was superior to 1HP (p<0.0001) and oral BDQ (p<0.0001 except p=0.05 for 62.5 mg/kg) and similar in magnitude to the same total DARQ dose given orally over 4weeks (Fig). Activity was dose-dependent for formulation B and similar for the 3 formulations at 125 mg/kg. Median DARQ Cmax was <1 µg/ml. Median AUC0-4w values were 137, 186 and 349 µg-h/ml and plasma concentrations were ≥36 ng/ml for 4, 6 and >6 weeks after the 62.5, 125 and 250 mg/kg doses of formulation B, respectively. Lung CFU and PK data at 8 and 12 weeks post-dose are pending.
Conclusions:
These data provide proof-of-concept for a highly efficacious pan-TPT regimen comprised of a single IM dose of an LAI DARQ formulation. Further preclinical development including studies to define the PK target, human dose estimates and GLP toxicology evaluation is highly warranted.
