Grant: Collaborative Health Research Projects (NSERC partnered)

Therapeutic drug monitoring (TDM) or clinical pharmacokinetic monitoring is important when a drug has a narrow therapeutic range; the pharmacokinetic parameters are unpredictable; and the drug assay will make a difference in the clinical decision-making process. A number of "chronic use" drugs (e.g., immunosuppressants, antiepileptics) and "acute use" drugs (e.g., anti-infectives) warrant TDM in clinical practice. TDM currently plays an important role for agents such as aminoglycosides, cyclosporine, tacrolimus, vancomycin, methotrexate, and others. Our aim is to develop a point-of-care system for the analysis of some of these drugs that is not based on blood sampling, but on extracting and analyzing interstitial fluid (ISF). We will develop a test method based on the ability of an array of microneedles to painlessly extract minute amounts of interstitial fluid from a patient's skin. A first drug candidate is methotrexate, an effective but also highly toxic drug used in cancer chemotherapy, rheumatoid arthritis, acute organ rejection, and other conditions. The methotrexate content of the interstitial fluid in the disposable microneedle chip will be determined using a specific enzymatic assay in a rapid and portable point-of-care instrument. The fabrication of the microneedles will use the solvent casting technology developed in Dr. Stoeber's lab to efficiently and inexpensively produce hollow microneedles appropriate for the extraction of interstitial fluid through capillary action. Dr. Hafeli will establish the correlation of interstitial fluid and blood levels of several drugs in a rabbit model and evaluate the microneedles in vivo. The close integration of the detection method for analysis of the interstitial fluid extracted with the microneedles will be performed by Dr. Stoeber, who has significant expertise in sensor development and microfluidic system integration. Dr. Ensom will perform a clinical trial to study the equivalence of interstitial and blood level measurements of methotrexate. She is also responsible for the pharmacokinetic analyses of patient and animal experiments. These studies are crucial, as there are currently no interstitial drug level measurements performed in the clinic. If our hypothesis is correct that interstitial drug levels are indicative for target organ drug concentrations and pharmacological effects, then the microneedle method is expected to revolutionize drug monitoring with a quick, pain- and bleeding-free method