Can Pharmacometabolomics and LC-HRMS develop a new Concept for Therapeutic Drug Monitoring?

Therapeutic drug monitoring (TDM) is a concept for individualized drug dosing that was developed into clinical routine as a consequence of research findings on variable drug effects and analytical technology developments made in the 1950th and onwards, and founded the clinical pharmacology discipline (1,2). TDM in practice is about measuring a specific drug concentration in blood, serum or plasma, but may also include pharmacogenetic and pharmacodynamic investigations (3). For some time big hopes were put on pharmacogenetics to help explain inter-individual variability in drug response. It is now realized that variability may occur over time and relate to influences from both inborn as well as environmental factors, and that a more multifactorial approach is needed for complex biological systems (4). Examples of important use of TDM comprise treatment of epilepsy, infection, psychiatric disease and immunosuppression after transplantation (1,5,6). Analytical methods for TDM were using immunochemical, HPLC and GC techniques for long time, but this has recently, but slowly, been challenged by LC-MS techniques (7). One good example of this is methods for the immunosuppressive drugs tacrolimus, ciclosporin, sirolimus and everolimus (8,9). LC-MS methods have offered significant improvements in the quality of analytical method performance. It has been demonstrated that LC-MS offer improvement in accuracy, precision and cost-effectiveness, and also can be made robust. With the use of LC-MS in LC-tandem MS SRM mode multi-component methods can be constructed with unique combination of selectivity and sensitivity. Analytical method demands in TDM are set by the requirements of accuracy, cost-effectiveness, rapid reporting and robustness in a routine laboratory environment.