August 9, 2022 -- A long-acting injectable formulation of rifabutin has delivered high plasma concentrations for 16 weeks in mice, resulting in the prevention of tuberculosis (TB) and the clearing of the pathogen from the lungs.
In a study published on August 8 in the journal Nature Communications, researchers from the University of North Carolina (UNC) at Chapel Hill describe the use of biodegradable polymers and biocompatible solvents to create a formulation that solidifies after subcutaneous injection and then gradually erodes to release the anti-TB drug rifabutin.
Administration of the formulation to mice resulted in plasma concentrations that were 10 times higher than the minimum inhibitory concentration (MIC) for at least four weeks after administration. Plasma concentrations stayed above the MIC for 16 weeks.
Current multidrug treatment regimens for cases of active drug-susceptible TB disease start with an intensive phase lasting two months, followed by a continuation phase of four months or longer. If the patient is unable to comply with the regimen, the treatment can fail to address the infection and contribute to the development of drug resistance. The burdens imposed on patients by existing regimens and the consequences of nonadherence point to an opportunity for more convenient therapies.
Recognizing those challenges, the UNC team set out to develop a long-acting formulation that could reduce the TB treatment regimen to one or two injections. The researchers contend they are on course to achieve their goal.
"We think our approach could dramatically change TB treatment," Martina Kovarova, PhD, associate professor of medicine at UNC, said in a statement. "Affordable long-acting formulations with generic anti-TB drugs would help ease the burden of this disease on low-income communities around the world where better access to treatment is most needed."
Kovarova and the rest of the team used the amphiphilic additives Kolliphor HS 15, TPGS, Tween 80, Tween 20, and Pluronic F68 and F127 to increase the solubility of rifabutin in dimethyl sulfoxide and n-methyl-2-pyrrolidone. The additives increased drug loads, decreased initial release bursts, and extended drug release in vitro and in vivo.
In mice, administration of 50 μL of RFB14KH, a formulation with lower release burst and extended drug release, resulted in plasma concentrations higher than those seen in humans when daily doses of 300 mg are given orally. Mean tissue-to-plasma ratios in the lung and spleen were higher than expected, "likely due to sustained drug delivery compared to the peak-to-trough drug concentration fluctuation in mice administered with repeated oral dosing."
Kovarova is now looking forward to phase I clinical trials that will begin the process of validating the use of long-acting rifabutin in the management of TB in humans.