Background
Tuberculosis (TB) is the leading cause of death in people with HIV. HIV is the single strongest risk factor for progression from latent TB infection to active TB disease. TB is fully curable disease, however, adherence to medication is essential for TB treatment success. Long-acting injectable (LAI) formulations with sustained drug release for months can reduce frequency of drug administration and improve adherence to medication. Here we developed LAI formulations of a recently approved anti-TB drug pretomanid and a novel second-generation diarylquinoline in development with a greater antimycobacterial activity and a potentially better safety profile compared to bedaquiline, TBAJ-876, using In Situ Forming Implant technology (ISFI).
Methods
Pretomanid (PA-ISFI) and TBAJ-876 (T876-ISFI) LAI formulations were optimized to have a high drug load and release drug for at least 2 months. Drug release properties of developed formulations were evaluated in vitro and in vivo. ISFI formulations were administered subcutaneously to BALB/c mice. Blood was collected from mice over a 12-week duration and plasma samples were analyzed for concentration of PA or TBAJ-876 using an appropriate LC-MS/MS method. Penetration to tissues relevant to TB infection was also evaluated 1- and 2-months post administration.
Results
A subcutaneous administration of 50mL PA-ISFI resulted in sustained release of PA that exceeded 2 months with a mean 2-month plasma concentration of 1095 ng/mL. Pretomanid penetrated tissues with mean tissue/plasma concentration ratios of 6.44 in lung, 5.38 in lymph nodes, and 4.30 in spleen. A subcutaneous administration of 50 mL of T876-ISFI resulted in sustained release of T876-ISFI that exceeded 3 months with a mean plasma concentration 727 ng/mL. TBAJ-876 penetrated into tissues at tissue/plasma concentration ratios of 27.1 in lung, 29.3 in lymph nodes, and 22.3 in spleen. A high level of the active N-desmethyl-TBAJ-876 (M3) metabolite was also observed in mouse plasma (1291 ng/mL) with tissue/plasma ratios of 80.3 in lung, 45.3 in lymph nodes, and 71.6 in spleen. Parent-to-M3 metabolite ratios in mouse tissues were 0.23 in lung, 0.40 in lymph nodes, 0.21 in spleen and 0.74 in plasma.
Conclusions
We successfully developed LAI formulations of pretomanid and TBAJ-876 that provide sustained drug release in vivo exceeding 8 weeks post administration in BALB/c mice with high drug penetration to tissues. Data presented here support further development of PA-ISFI and T876-ISFI formulations.