Breaking the therapeutic drug monitoring logistics barrier.

Therapeutic drug monitoring (TDM) is one of the most complex laboratory testing processes in modern laboratory medicine practice. Based on the simple engineering principle of feedback control, TDM strives to regulate an individual’s exposure to a drug by measuring the drug’s concentrations, usually at steady state and at distributional equilibrium, and then use these concentrations to determine the drug’s new dose. Unlike a thermostat in a home that can measure temperature in real time and trigger the introduction of more heat from a furnace until a target temperature is reached, drug concentration monitoring currently requires multiple steps, including administration of a drug at the correct dose, collection of one or more blood samples at precise times following drug administration, transport of these samples to a laboratory where they can be analyzed, and then returning the concentration results to a physician, who can then adjust the future dose. Moreover, the exposure to a drug is often estimated through fitting of sparsely sampled concentration data to pharmacokinetic models that are sometimes complex. In some cases, only a single trough concentration can be practically collected due to the busy nature of many outpatient clinics. Successful TDM, therefore, requires that a team comprising a physician, pharmacist, nurse, phlebotomist, and laboratory professional all work closely together to coordinate and perform this complex monitoring process correctly (1 ). Each step in this complex process affords the possibility of error, and error is always inevitable. Controlling error in the total testing process is tantamount to TDM success. Laboratory accreditation and proficiency testing programs, along with innovations in laboratory technology, have done a remarkable job of improving the quality of clinical laboratory testing. The analytical error (combined imprecision and bias) for TDM tests is often well below 10% for most measured drugs. Drug manufacturers and pharmacists also apply rigorous QC and quality assurance principles to assure that an accurate dose of a medication is provided to patients. In between the administration of a drug and analysis of its concentration in the laboratory exists a proverbial “TDM black box,” in which the timing of blood collection in relationship to drug administration is often subject to great uncertainty. This is due in no small part to the complicated logistics of coordinating dosing with sample collection in the busy clinical setting. For many drugs, this uncertainty can render the whole TDM process useless and perhaps even dangerous, representing the greatest challenge to successful application of TDM (2 ). The recent study reported by Ferguson et al. in Science Translational Medicine represents a possible way to crack open the TDM black box and perhaps make TDM far more clinically useful (3 ). These investigators describe a Lab-on-a-Chip device termed microfluidic electrochemical detection for in vivo continuous monitoring (MEDIC). This device combines a novel microfluidics system with a DNA aptamer-based electrochemical biosensor to continuously measure small molecules. Taking advantage of the changes in secondary structure of a DNA aptamer upon binding to a small molecule like a drug, Ferguson et al. show the ability of gold-immobilized aptamers to transduce an electrochemical signal in proportion to the concentration of the aptamer-binding drug in whole blood. Most impressively, they demonstrate the feasibility of applying this technology to the real-time in vivo monitoring of the distributional pharmacokinetics of the free concentrations of 2 drugs, doxorubicin (4 ) and kanamycin, in rats over the course of 4 h. DNA aptamers are one of the key components of the MEDIC device. Aptamer technology, which has been around for close to 2 decades, provides a platform for generating nucleic acid polymers capable of specific and high-affinity binding to a wide range of molecules. Serving as an alternative to antibodies, aptamer technology has a particularly attractive feature, the ability to readily generate specific RNA or DNA aptamers through the screening of a randomly generated oligonucleotide library (often termed selective evolution of ligands by exponential enrichment, or SELEX) over the 1 Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA. * Address correspondence to this author at: Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Founders Pavillion 7.103, Philadelphia, PA 19104. Fax 215-662-7529; e-mail [email protected]. upenn.edu. Received May 27, 2014; accepted May 29, 2014. Previously published online at DOI: 10.1373/clinchem.2014.222935 2 Nonstandard abbreviations: TDM, therapeutic drug monitoring; MEDIC, microfluidic electrochemical detection for in vivo continuous monitoring. Clinical Chemistry 60:12 000 – 000 (2014) Perspectives