Over the past decade, drug development failures attributed to poor pharmacokinetics have dramatically decreased from over 40% to around 10%. This is mainly due to the increasing availability of medium and high-throughput in vitro ADME screens (Absorption, Distribution, Metabolism, and Excretion) as well as an earlier focus on pharmacokinetic (PK) properties during the discovery process. The Pharmacology Unit collaborates closely with the Chemistry group during the hit-to-lead and lead optimization phases to ensure acceptable PK properties of the selected molecules that are designed, synthesized and purified by the medicinal chemists. This is initially accomplished using a battery of in vitro assays, followed by in vivo PK assessment of the compounds in rodents to evaluate their oral bioavailability and overall systemic exposure. We support the PK evaluation of novel compounds for the Dengue, Tuberculosis and Malaria drug discovery programs.
In parallel, we have launched several research projects aimed at addressing some of the most crucial gaps in TB drug discovery. Specifically, we are developing a novel rat model of TB infection, in collaboration with the Pasteur Institute - Brussels (P. Bifani), to answer the lack of a rapid, convenient and cost effective animal model in a species that is also widely adopted for PK and Toxicology evaluation in Pharma.
It takes 6 to 24 months of intensive combination therapy to cure TB with antibiotics that have proven activity in vitro. In contrast, many pulmonary infectious diseases can be cured following single drug treatment with similar drugs for only one to a few weeks. Besides the persistence phenomenon and the unique immunopathology of M. tuberculosis, we hypothesize that some TB drugs may have poor lesion penetration properties and therefore not reach their site of action effectively. This aspect of the TB drug pharmacokinetics has been largely neglected so far. In collaboration with colleagues at Novartis-Basel and several groups with worldwide expertise in animal models of TB infection, we plan to study and model drug penetration into TB lesions using various bio-imaging technologies such as Scanning Mass Spectrometry.
Finally, clinical endpoints relying on relapse rates for the evaluation of new anti-TB chemotherapy require large cohorts and prolonged follow-up of patients, a major hurdle for the development of new drugs. In collaboration with the NIH, the National Masan TB Hospital in Korea, the National University of Singapore and the Singapore Bio-Imaging Consortium, we plan to identify and validate biomarkers of treatment response in the fields of lipidomics, immune responses, and imaging of inflammation, lesion types and microbiological characteristics.
The Pharmacology Unit is composed of three groups: In vivo Pharmacokinetics, headed by Suresh B Lakshminarayana, Bioanalytics, headed by Anne Goh, and Biomarkers and Translational Research, headed by Maxime Hervé.
Scientific Collaborations of Pharmacology Research at NITD:
