UCSF

TBI-223 Model for Human Translation

The Savic Lab is building a TBI-223 model for human translation. Linezolid (LZD), an antibiotic of the oxazolidinone family, has demonstrated great utility in the treatment of multi-drug and extreme drug-resistant tuberculosis. Its high hematological and bone marrow suppression toxicities have, however, limited its use, especially in the treatment of tuberculosis infections that require high doses over long periods of time to treat mycobacteria. A promising compound of the same oxazolidinone class, TBI-223, being developed by the TB Alliance shows great promise as a potential substitute for linezolid; it has similar potency and efficacy without the hematological and bone marrow toxicities caused by other compounds within the same class. TBI-223 is making progress toward its first human trial, which is expected to proceed within the next 18 months. Using compiled animal data from mouse, rat, dog, and monkey species, our lab has built a comprehensive pharmacokinetic model that allometrically scales the nonlinear elimination of TBI-223 to accurately predict safe first in-human doses. Our lab applied the same model strategy to linezolid to investigate how well modeling could predict human pharmacokinetics and found this model aligns well with clinical pharmacokinetics. The project is now continuing with PK/PD modeling to predict in-human drug efficacy using mouse data from lab collaborators Eric Nuermberger and Kelly Dooley of Johns Hopkins University.