Abstract

Applications of LC-MS/MS to Therapeutic Drug Monitoring: Recent Developments and Future Directions for a Personalized Medicine

Laurent Decosterd, Associate Professor, Universite de Lausanne

There are increasing efforts at getting better and more secure use of drugs by increasing our understanding of the existing link between drug’s pharmacokinetics (its fate in the body) and pharmacogenetics (genetic traits that influence drug disposition) and the response (or absence of response) and/or the toxicity elicited by drug treatment. It has been established over the last decades that the therapeutic use of some drugs could be optimized by an individualization of their dosage, based on blood concentrations measurement. This feedback strategy, termed Therapeutic Drug Monitoring (TDM) is now current practice for antiepileptics, immunosuppressive drugs, anti-HIV and antifungal drugs, for some antibiotics drugs, and more recently, for new anticancer targeted drugs. TDM is generally considered for drugs with large inter-individual but limited intra-individual pharmacokinetic variability, with both consistent concentration-efficacy (and concentration-toxicity) relationships. Overall, TDM is now considered in case of therapeutic failure, adverse drug reactions, drug interactions problems, doubt on patient’s compliance and in several special clinical conditions (pregnancy, pediatrics, hepatic and renal failure, Intensive Care Unit, etc) In that context, the technique of chromatography coupled to tandem mass spectrometry (LC-MS/MS) has become an essential component for the development of high throughput multiplex assays to respond efficiently to the increasing number of analytical demands and their application for the TDM of current and new classes of anti-HIV drugs, antifungals, antibiotics, new antiepileptics and targeted anticancer agents, as well as new antimalarial combinations regimens. In the emerging field of Personalized Medicine, application of LC-MS/MS accompanied with TDM interpretations offer the possibility of patient-tailored drug dosage adjustments which should allow to maximize both the therapeutic benefit and the tolerability of drugs in patients.