Long-acting formulations for the treatment of latent tuberculous infection: opportunities and challenges

Abstract

SUMMARY Long-acting/extended release drug formulations have proved very successful in diverse areas of medicine including contraception, psychiatry, and most recently, HIV disease. While challenging, application of this technology to TB treatment could have substantial impact. The length of treatment required for all forms of TB put existing regimens at risk for failure because of early discontinuations and treatment default. Long-acting injections, for example administered monthly, could improve patient adherence and treatment outcomes. We review the state of the science for potential long-acting formulations of existing TB drugs, and propose a Target Product Profile for new formulations to treat latent TB infection. The physicochemical properties of some TB drugs make them unsuitable for long-acting formulation, but there are promising candidates that have been identified through modeling and simulation, and other novel agents and formulations in preclinical testing. An efficacious long-acting treatment for latent TB infection, particularly for those co-infected with HIV, and if coupled with a biomarker to target those at highest risk for disease progression, would be an important tool to accelerate progress towards TB elimination.

New opportunities in tuberculosis prevention: implications for people living with HIV

“…Future TPT options include long‐acting drug formulations, with the potential benefit of extended duration for drug delivery that could lead to improved adherence and outcomes . Precedents come from the HIV therapy field and the development of an injectable combination of rilpivirine/cabotegravir that can be administered every one to two months, and ongoing studies of other injectable formulations such as cabotegravir for pre‐exposure prophylaxis . Since 2015, a working group on long acting/extended release formulations for TB prevention and treatment was established under the umbrella of the Long‐Acting/Extended Release Antiretroviral Resource Programme (LEAP) .…”

Activity of a Long-Acting Injectable Bedaquiline Formulation in a Paucibacillary Mouse Model of Latent Tuberculosis Infection

“…Although highly efficacious regimens exist for the treatment of LTBI, low treatment completion rates hinder their practical effectiveness (2, 6, 7, 36). The use of LAI drug formulations for LTBI treatment could simplify treatment and improve completion rates (9). It may also overcome limitations of poor or variable oral bioavailability, mitigate concentration-dependent toxicity and drug-drug interactions, and ease administration in children.…”

“…Beyond decreasing regimen durations, another modification with the potential to significantly reduce the burden on health care delivery systems and improve LTBI treatment completion rates is the use of long-acting injectable (LAI) formulations for drug administration (9). The development and administration of LAI and implantable drug formulations have improved adherence, i.e., there are fewer missed daily doses following injection, compared to that with daily oral drug intake in patients receiving antipsychotic medications (10) and in individuals using hormone-based contraceptives (11).…”

“…Two key properties of (pro)drugs administered in LAI formulations are low aqueous solubility, to preclude the rapid dissolution and release of the active drug substance, and a reasonably long pharmacokinetic (PK) elimination half-life, i.e., slow clearance from the body (21). For an antimicrobial, another desired property is high potency, negating the need for high concentrations in the blood (9) and allowing low drug doses to be injected. The diarylquinoline bedaquiline, which has a low MIC for M.…”

“…The diarylquinoline bedaquiline, which has a low MIC for M. tuberculosis (about 0.03 μg/ml), high lipophilicity (logP, 7.3), and a long half-life (about 24 h, functionally or effectively), possesses a profile that may be suitable for use in an LAI formulation (9, 22–25). Furthermore, bedaquiline has been shown to specifically contribute significant treatment-shortening activity in mouse models of TB (26–28) and is associated with treatment shortening in patients with multidrug-resistant (MDR) TB (29–31), suggesting that this drug could also contribute treatment-shortening activity to an LTBI treatment regimen.…”