A long-acting formulation of rifabutin is effective for prevention and treatment of Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis (Mtb) and is a major cause of morbidity and mortality. Successful treatment requires strict adherence to drug regimens for prolonged periods of time. Long-acting (LA) delivery systems have the potential to improve adherence. Here, we show the development of LA injectable drug formulations of the anti-TB drug rifabutin made of biodegradable polymers and biocompatible solvents that solidifies after subcutaneous injection. Addition of amphiphilic compounds increases drug solubility, allowing to significantly increase formulation drug load. Solidified implants have organized microstructures that change with formulation composition. Higher drug load results in smaller pore size that alters implant erosion and allows sustained drug release. The translational relevance of these observations in BALB/c mice is demonstrated by (1) delivering high plasma drug concentrations for 16 weeks, (2) preventing acquisition of Mtb infection, and (3) clearing acute Mtb infection from the lung and other tissues.

Using dynamic oral dosing of rifapentine and rifabutin to simulate exposure profiles of long-acting formulations in a mouse model of tuberculosis preventive therapy

“…Our exposure-activity data for rifabutin align with that reported by Kim et al, who found that a long-acting biodegradable in situ forming implant of rifabutin that maintained plasma concentrations above 0.064 μg/mL, a reported ECOFF concentration (17,18) selected as a target for up to 18 weeks post-injection, exhibited potent anti-TB activity in mouse models (13). The formulation developed by Kim et al is therefore especially promising given that our data suggest that far lower target concentrations of rifabutin may be sufficient for efficacy in TPT regimens.…”

“…The physiochemical properties of another rifamycin antibiotic, rifabutin, appear even more favorable than rifapentine for LAI formulation (5,8). Although only currently indicated for prevention and treatment of nontuberculous mycobacterial disease (9,10), rifabutin has demonstrated potent anti-TB activity in preclinical models, including preclinical models of TPT (11)(12)(13)(14)(15), and has been used off-label for prevention and treatment of TB (reviewed in (16)). The suitability of rifabutin as a long-acting formulation is highlighted in a recent publication by Kim et al describing the development of long-acting biodegradable in situ forming implants of rifabutin (13).…”

Progress in Treatment and Diagnostics of Infectious Disease with Polymers

“…A long acting injectable of PLGA was developed to deliver rifabutin, which solidifies after subcutaneous injection. In vivo results show high plasma drug concentration and quick clearance of M.tb from lungs . In this direction, Table shows the clinical and preclinical status of various TB vaccines.…”

“…In vivo results show high plasma drug concentration and quick clearance of M.tb from lungs. 58 In this direction, Table 3 shows the clinical and preclinical status of various TB vaccines.…”

Hyaluronidase impacts exposures of long-acting injectable paliperidone palmitate in rodent models

“…Paliperidone palmitate was used as a representative approved and marketed LAI formulation for which PK and drug depot histopathology data in rat models were published [10,11]. In this study, we also included assessment in a mouse model, as mouse models are often used in pre-clinical treatment models of infectious diseases, including mouse models of tuberculosis used to evaluate developmental LAI formulations of anti-tuberculosis drugs [12][13][14].…”