Project Summary:

In the late 1990s, the pharmaceutical industry realized that more than 40% of drug candidates failed in clinical development because of poor pharmacokinetics (PK) properties. Pharmacokinetics can be defined as the fate of a drug in the human body, how it is absorbed from the gastro-intestinal tract into the blood compartment, distributed into tissues, metabolized in the liver and eliminated through the bile or kidneys. This high attrition rates associated with unfavorable PK caused extremely costly late-stage failures in drug development. Since then, it has become widely appreciated that PK and toxicological evaluation should be considered as early as possible in the drug discovery process. With the integration of in vitro assays of absorption, distribution, metabolism and elimination (ADME), in vitro toxicity assays and rodent studies, PK- and toxicity-related factors have been dramatically reduced as a cause of attrition in drug development. Our group will leverage a fully integrated analytical platform and state-of-the-art animal facility available at the Regional Biocontainment Lab of the PHRI (Newark, NJ) to assist the CETR consortium in developing therapeutic countermeasures to high-threat bacetrial agents. The Core B Leader, Dr Véronique Dartois, has extensive experience in the pharmacological evaluation of anti-infective compounds, acquired through 7 years in the field of neglected disease drug development. We will evaluate the pharmacokinetic, tolerability and tissue penetration properties of compounds to assist in early drug discovery stages (hit triage, hit-to-lead and lead optimization), and reduce attrition rates related to poor pharmacokinetic, toxicity and unfavorable tissue distribution characetristics.


Véronique Dartois joined PHRI in April 2012, with an academic appointment in the Department of Medicine at Rutgers, the State University of New Jersey. Initially trained as a molecular biologist, Dr Dartois comes with 7 years of experience in the pharmaceutical industry, acquired through her previous position as Pharmacology Unit Head at the Novartis Institute of Tropical Diseases in Singapore. Her current research interests include the pharmacokinetics and imaging of anti-tuberculosis drugs in pulmonary lesions, the molecular mechanisms driving intracellular accumulation of TB drugs in Mycobacetrium and in macrophages, and the optimization of predictive animal models and in vitro assays to study these questions.

With funding from the Gates Foundation and the NIH, research activities in the Dartois lab focus on the pharmacokinetics and pharmacodynamics of anti-tuberculosis agents in pulmonary TB lesions, in the rabbit model and through clinical research studies. Specifically, lesion-specific analysis of drug exposure and bacetrial killing help identify and characetrize lung granuloma compartments in which organisms are not eliminated. In the context of failing TB control programs and global emergence of drug resistance, this information can guide a more rational approach to designing treatment regimens that ensure optimal drug exposure at the site of infection. Recent reports suggesting that many of the 1st line drugs may be sub-optimally dosed highlight the importance of these studies.

A state-of-the-art Imaging Mass Spectrometry (IMS) platform is now available in the Dartois Lab, for the visualization of drugs and metabolites in biological tissues. IMS preserves spatial profile and tissue architecture, enabling the relative quantification and 2D distribution of the drugs and their metabolites within healthy and diseased tissues. The group combines the accuracy of conventional mass spectrometry with the spatial resolution of IMS to measure the levels of anti-tuberculous agents in various lesion types versus uninvolved lung tissue and plasma, and visualize relative drug distribution and concentration gradients across the different layers of individual granulomas and cavities. This technology can be expanded to a large variety of drug molecules active against an array of diseases, and holds great promise for the molecular imaging of the biochemical and pathological changes caused to the host by any disease of interest. 

Contact info:

Veronique Dartois, PhD
Associate Professor
New Jersey Medical School

PHRI Center
ICPH Building
225 Warren Street
RBL Room 2230
Newark, NJ  07103

Tel.   (973) 854-3160
Fax.  (973) 854-3101