The translational biomarkers focus group seeks to interact with other NIPTE faculty to identify additional areas of pharmaceutical science that could interface with the generation and application of translational biomarkers.
The translational biomarkers focus group is concerned with the end usage of pharmaceutical products in relation to their safety, efficacy, and quality. The focus group combines the professional experience in pharmacogenetics and mass spectrometry-based metabolomics of NIPTE faculty. These activities are harnessed to identify metabolomic biomarkers in animal and cell culture models that can be translated to patients treated with drugs that display intersubject variability in efficacy and toxicity. However, in many cases, relatively little is known about the cellular processes that link drug plasma levels to adverse drug reactions (ADRs). Genetic factors contribute to the interpatient variability in drug and metabolite plasma profiles that determine both wanted and unwanted drug responses for a wide range of therapeutic agents. Of particular interest is the observation that patients often display a discordance between their actual drug plasma levels and those predicted based purely upon genetic factors. This is because drug metabolism and disposition is not simply determined by genotype. Other relevant variables including liver and kidney function, hemodynamics, diet, aging, the gut microbiota, and pharmaceutical formulation can all influence drug pharmacokinetics and therefore drug responses.
These aforementioned variables and many others impact upon endogenous metabolic pathways and networks. They can therefore be interrogated using metabolomic techniques which, in a practical sense, determine as many metabolites as possible in biofluids such as plasma and urine. We propose that such metabolomic profiles can act as biomarkers that enhance the interpretation of pharmacogenetic factors in relation to drug efficacy and safety considerations. Moreover, these biomarkers will also provide new insights into the cellular mechanisms underlying drug toxicity. We have developed protocols in mouse models using mass isotopomer-guided metabolomics for the discovery of novel biomarkers of drug efficacy and toxicity. These methodologies could also be applied using cell culture systems, although this is currently untested. Translation of these biomarkers to patients is expected to yield protocols for the prediction of ADRs and enhance ongoing efforts that employ pharmacogenetic variables.
The advantages of this focus of activity to public health and the FDA include: new knowledge on the biochemical and genetic mechanisms of ADRs, generation of predictive biomarkers for target organ toxicities (e.g. CNS and cardiovascular), protection of the public from ADRs, improvement in safety and efficacy of human drugs, guidance for dose- ranging in clinical trials, minimization of drug failures and withdrawals, facilitation of the approval process for new drugs and formulations, modernization of toxicology, and the enhancement of product safety.