Project overview
As is highlighted in our LONGEVITY Tuberculosis (TB) page, TB and latent tuberculosis infection (LTBI) is having a devastating impact across the globe. This is especially true in low- and middle- income countries (LMICs) where TB is disproportionate in both prevalence and morbidity. Preventing diseases is always preferable over treating a patient who has contracted it. Thus, TB preventative therapy (TPT) is incredibly important in the effort to control the effect of this disease.
The dosing regimens for TPTs are often demanding, requiring daily oral doses over the course of months. When doses are missed it dramatically reduces how well the drug works in preventing the disease. Creating long-acting formulations of drugs that already exist could alleviate the pill burden of current TPTs. This will take some time, as currently these medicines are only available as oral medications.
Oral rifapentine has well characterised anti-tuberculosis properties. We also know what plasma concentrations need to be achieved for the oral drug to be effective. However, what we didn’t know was what the long-acting injectable (LAI) plasma profile looks like to achieve this, as there hasn’t been a rifapentine LAI yet. We needed to determine what exposure profiles, on the necessary timescale, would work to give efficacy if it were given as a long-acting formulation TPT.
It is key to know what concentrations of a drug need to be achieved and maintained in plasma to be effective at preventing TB. This is so we can understand what dosing regimens are needed to keep plasma concentrations safely at those levels. Once that information is understood, work can begin to create and characterise a long-acting version of the medication. A long-acting therapeutic will keep the levels of the medications at the right concentration over a longer period of time.
CELT's objectives
- To determine exposure-activity profiles of rifapentine to inform development of LAI formulations for TPT:
- Learn and confirm the target rifapentine plasma concentrations needed in TB infected mice, in order for these drugs to be effective in treating TB on a long-acting TPT timescale of 1-2 months.
- While the LAI formulation is in development; design and test an oral dosing regimen in TB infected mice that will have a predicted concentration profile similar in shape and duration to that expected for a LAI regimen. This will achieve the exposures that are expected to be needed for efficacy. All of this will demonstrate that efficacy with such an exposure profile for a LAI TPT is feasible. - To create and characterise a formulation to achieve and maintain a rifapentine exposure profile expected to be efficacious against TB, using long-acting injections a few weeks to a month apart:
- Determine how long rifapentine dosed as the novel formulation will take to be absorbed and then remain in mice, while being metabolised and excreted, with an initial pharmacokinetics (PK) study examining exposure alone.
- Using data analysis and modelling of the initial PK study, we will set doses/regimens for the LAI formulation. These will be expected to achieve the required target exposure profile for efficacy on the timescale required.
- Use a TB-infected mouse pharmacodynamics (PD) study to demonstrate and understand what rifapentine, dosed as the novel LAI formulation under the chosen regimens, will do over a 1-2 month timescale
Project findings
- Oral dosing administered to produce a LAI-like exposure profile showed promising efficacy for rifapentine in treatment of TB.
- The subsequently developed long-acting injectable formulation showed efficacy against TB over periods of 4 to 8 weeks. This included various regimen designs chosen based on its initial PK characterisation. Efficacy was shown to different degrees, at different dose levels, following a single injection, two injections 14 days apart, and an injection every 4 weeks.
Project implications
This work was proof of concept that a LAI rifapentine formulation could successfully be used to treat TB in mice under a variety of dosing regimens. Use of PK modelling and simulation allowed for informed regimen design. This included the potential to use an alternate oral dosing route/format to test an expected PK exposure profile that might be achieved by a LAI.
The long-acting rifapentine formulation is now moving on to toxicology studies. This stage makes sure that the long-acting versions are as safe for patients as the oral regimens already on the market. From there, we can look for funding for manufacturing scale up to move to clinical trials in human volunteers.
Long-acting preventative TB treatments being easily available in the places they are needed most will hopefully ease the difficulty people encounter with current TB prevention medications. This is a big step towards helping eradicate the TB burden by making preventative therapy easier to disseminate and access in LMICs, where it is causing the most devastation.
Awarding body
(P30AI094189)
(2020-38-LONGEVITY)
Related publications
- Using Dynamic Oral Dosing of Rifapentine and Rifabutin to Simulate Exposure Profiles of Long-Acting Formulations in a Mouse Model of Tuberculosis Preventive Therapy
Chang, Y.S., Li, S.Y., Pertinez, H., et al. (2023) - CROI Poster | Long-Acting Injectable Rifapentine With Activity in a Mouse Model of Tuberculosis Preventive Therapy
Pertinez, H., Ammerman, N.C., et al. Poster 880, presented by Pertinez, H. (2024)